WO2023176867A1 - Method for producing 2-acetyl-1-pyrroline - Google Patents
Method for producing 2-acetyl-1-pyrroline Download PDFInfo
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- WO2023176867A1 WO2023176867A1 PCT/JP2023/009990 JP2023009990W WO2023176867A1 WO 2023176867 A1 WO2023176867 A1 WO 2023176867A1 JP 2023009990 W JP2023009990 W JP 2023009990W WO 2023176867 A1 WO2023176867 A1 WO 2023176867A1
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- the present invention relates to a method for producing 2-acetyl-1-pyrroline.
- 2-Acetyl-1-pyrroline is known as a useful aromatic component in various foods such as rice and bread, and is an important compound in the food industry.
- Various synthetic methods have been disclosed for 2-acetyl-1-pyrroline. For example, the following two cases have been published.
- the present inventors set it as a task to develop a new method for synthesizing 2-acetyl-1-pyrroline.
- the first invention of the present application is "A method for producing 2-acetyl-1-pyrroline comprising a reaction step of N-(tert-butoxycarbonyl)-L-proline and N,O-dimethylhydroxylamine.”
- the above reaction is preferably carried out using N-(tert-butoxycarbonyl)-L-proline, 1,1-carbonyldiimidazole and N,O-dimethylhydroxylamine hydrochloride. That is, the second invention of the present application is 2- according to claim 1, wherein the reaction step is carried out by a reaction step of N-(tert-butoxycarbonyl)-L-proline, 1,1-carbonyldiimidazole and N,O-dimethylhydroxylamine hydrochloride. "Method for producing acetyl-1-pyrroline.”
- N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine is obtained by a Grignard reaction.
- the third invention of the present application is “A reaction step for obtaining N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine by a Grignard reaction after the reaction step of the N-(tert-butoxycarbonyl)-L-proline and N,O-dimethylhydroxylamine.
- the method for producing 2-acetyl-1-pyrroline according to claim 1 or 2 which comprises:
- the Grignard reaction is preferably carried out using methylmagnesium bromide. That is, the fourth invention of the present application is "The method for producing 2-acetyl-1-pyrroline according to claim 3, wherein the Grignard reaction is carried out by a reaction step with methylmagnesium bromide.”
- the fifth invention of the present application is “2-acetyl-1-pyrrolidine according to claim 3 or 4, comprising a reaction step of obtaining 2-acetyl-1-pyrroline by deprotecting and oxidizing the N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine.
- the sixth invention of the present application is: “A method for producing 2-acetyl-1-pyrroline comprising the following steps (A) to (D).
- 2-acetyl-1-pyrroline can be easily produced without requiring cryogenic conditions or high pressure conditions. This makes it possible to provide 2-acetyl-1-pyrroline in various industrial fields, including the food industry.
- FIG. 1 is a diagram showing the overall steps of the method for producing 2-acetyl-1-pyrroline of the present invention.
- FIG. 1 is a diagram showing the first step of the method for producing 2-acetyl-1-pyrroline of the present invention.
- FIG. 3 is a diagram showing the second step of the method for producing 2-acetyl-1-pyrroline of the present invention.
- FIG. 3 is a diagram showing the third and fourth steps of the method for producing 2-acetyl-1-pyrroline of the present invention.
- An example of the method for producing 2-acetyl-1-pyrroline of the present invention is a method that involves the steps shown in FIG. 1, for example.
- compounds 1 to 5 are as follows.
- This step is a step of amidating compound 1: BOC-L-proline.
- the present invention is characterized by this step. With L-proline bound to a tert-butoxycarbonyl protecting group, the carboxyl group of L-proline is reacted with N,O-dimethylhydroxylamine to form an amide.
- BOC-proline by treating it with di-tert-butyl dicarbonate (Boc2O) or the like as a starting material for L-proline.
- the acyl group of the carboxy group of BOC-L-proline can be transferred to the amine using carboxyimidazole, thionyl chloride, or the like.
- carboxyimidazole it is preferable to carry out the reaction at room temperature, and in the case of thionyl chloride, it is preferable to carry out the reaction at about 5 to 10°C.
- the amide of N,O-dimethylhydroxylamine is sometimes referred to as Weinreb amide.
- N-(tert-butoxycarbonyl)-L-proline is reacted with N,O-dimethylhydrokylamine to form compound 2 (N-methyl-N-(N-(tert-butoxycarbonyl)- (L-prolyl)-O-methylhydrokylamine).
- the substrate equivalent when BOC proline is approximately 1, it is preferable that carboxyimidazole and N,O-dimethylhydrokylamine be approximately 1.2 equivalents.
- ⁇ Second step (Grignard reaction)
- the compound 2 N-methyl-N-(N-(tert-butoxycarbonyl)-L-prolyl)-O-methylhydrokylamine
- the amide is decomposed by reacting 2 with a Grignard reagent to produce a ketone.
- the side reaction in which alcohol is produced can be suppressed by reacting the ketone produced again with the Grignard reagent.
- a Grignard reagent is prepared from halogenated methyl and metallic magnesium, and the Grignard reagent is converted into compound 2 (N-methyl-N-(N-( tert-butoxycarbonyl)-L-prolyl)-O-methylhydrokylamine).
- the addition method include a method of dropping a Grignard reagent onto the compound obtained in the first step.
- methylmagnesium bromide or methyl is a method of reacting magnesium chloride. This allows the amide to be decomposed to prepare compound 3 (N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine).
- N-(tert-butoxycarbonyl)-2-propionyl-pyrrolidine can be obtained, and 2-propionyl-1-pyrrolidine can be produced from this. You can also do it.
- the substrate equivalent weight is approximately 1 for compound 2 ((N-methyl-N-(N-(tert-butoxycarbonyl)-L-prolyl)-O-methylhydrokylamine) and 2.1 for methylmagnesium bromide. It is preferable to use about an equivalent amount.
- N-(tert-butoxycarbonyl) which is the nitrogen protecting group of the pyrrolidine obtained in the second step, is deprotected.
- a method of adding trifluoroacetic acid or hydrochloric acid, a hydrogen chloride/ethyl acetate solution, a hydrogen chloride/dioxane solution, a hydrogen chloride/cyclopentyl methyl ether solution, etc. can be used.
- compound 3 N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine
- a deprotection reaction by dropping trifluoroacetic acid to prepare 2-acetyl-pyrrolidine.
- One method is to do so.
- 2-acetyl-1-pyrroline can be prepared by oxidizing 2-acetyl-pyrrolidine obtained in the third step.
- Various methods can be selected for the oxidation step; for example, oxygen can be used as the oxidizing agent. Additionally, other methods include chromic acid oxidation, TEMPO oxidation, Dess-Martin oxidation, Oppenauer oxidation, etc.
- FIG. 3 shows the second step.
- a saturated aqueous sodium hydrogen carbonate solution was added to the obtained reaction crude of Compound 4 so that the reaction solution became neutral.
- the reaction solution was placed in an oxygen atmosphere and stirred for 1 hour. After confirming the disappearance of the raw materials using GC, the reaction solution was returned to room temperature, and the reaction solution was extracted three times using diethyl ether (20 ml). After drying the obtained organic layer using sodium sulfate, the reaction solution was concentrated using an ice bath under reduced pressure. At this time, the GC purity of Compound 5 (2-acetyl-1-pyrroline) at the time of concentration was 89%.
- FIG. 4 shows the third and fourth steps.
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Abstract
[Problem] To develop a new method for producing 2-acetyl-1-pyrroline. [Solution] 2-acetyl-1-pyrroline can be favorably produced through the step of reacting N-(tert-butoxycarbonyl)-L-proline with N,O-dimethylhydroxylamine. The reaction step is preferably a step in which N-(tert-butoxycarbonyl)-L-proline is reacted with 1,1-carbonyldiimidazole and N,O-dimethylhydroxylamine hydrochloride. By this production method, 2-acetyl-1-pyrroline can be easily produced.
Description
本発明は2-アセチル-1-ピロリンの製造方法に関するものである。
The present invention relates to a method for producing 2-acetyl-1-pyrroline.
2-アセチル-1-ピロリンは米やパン等の各種の有用な香気成分として知られており、食品産業において重要な化合物である。2-アセチル-1-ピロリンについては従来まで種々の合成方法が開示されている。例えば、以下の２件が公開されている。
2-Acetyl-1-pyrroline is known as a useful aromatic component in various foods such as rice and bread, and is an important compound in the food industry. Various synthetic methods have been disclosed for 2-acetyl-1-pyrroline. For example, the following two cases have been published.
上記の先行技術文献には2-アセチル-1-ピロリンの有効な製造方法が開示されている。
一方、特許文献１の先行技術では、当該特許文献に記載の工程(C)において、2-（メトキシカルボニル）-1-ピロリンをハロゲン化マグネシウムメチルにより処理するが、当該グリニャール反応の際に－45℃という低温条件が必要となっている。
次に、特許文献２の先行技術では、Step Aの2-アセチルピロールを還元（水素化）し、1-（ピロリジン-２-イル）エタノールを得る還元反応の工程において高圧状態にする必要があった。
The above-mentioned prior art documents disclose effective methods for producing 2-acetyl-1-pyrroline.
On the other hand, in the prior art of Patent Document 1, in step (C) described in the Patent Document, 2-(methoxycarbonyl)-1-pyrroline is treated with magnesium methyl halide, but during the Grignard reaction, -45 A low temperature condition of ℃ is required.
Next, in the prior art of Patent Document 2, it is necessary to create a high pressure state in the reduction reaction process of Step A, in which 2-acetylpyrrole is reduced (hydrogenated) to obtain 1-(pyrrolidin-2-yl)ethanol. Ta.
一方、特許文献１の先行技術では、当該特許文献に記載の工程(C)において、2-（メトキシカルボニル）-1-ピロリンをハロゲン化マグネシウムメチルにより処理するが、当該グリニャール反応の際に－45℃という低温条件が必要となっている。
次に、特許文献２の先行技術では、Step Aの2-アセチルピロールを還元（水素化）し、1-（ピロリジン-２-イル）エタノールを得る還元反応の工程において高圧状態にする必要があった。
The above-mentioned prior art documents disclose effective methods for producing 2-acetyl-1-pyrroline.
On the other hand, in the prior art of Patent Document 1, in step (C) described in the Patent Document, 2-(methoxycarbonyl)-1-pyrroline is treated with magnesium methyl halide, but during the Grignard reaction, -45 A low temperature condition of ℃ is required.
Next, in the prior art of Patent Document 2, it is necessary to create a high pressure state in the reduction reaction process of Step A, in which 2-acetylpyrrole is reduced (hydrogenated) to obtain 1-(pyrrolidin-2-yl)ethanol. Ta.
そこで、本発明者らは2-アセチル-1-ピロリンの新たな合成方法を開発することを課題とした。
Therefore, the present inventors set it as a task to develop a new method for synthesizing 2-acetyl-1-pyrroline.
本発明者らの鋭意研究の結果、BOC-L-プロリン（Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリン）を利用し、当該BOC-L-プロリンをＮ,O-ジメチルヒドロキシルアミンとの反応によって得られる反応物を利用することによって好適に2-アセチル-1-ピロリンを製造できることを見出し、本発明を完成するに至ったのである。
As a result of intensive research by the present inventors, using BOC-L-proline (N-(tert-butoxycarbonyl)-L-proline), the reaction of the BOC-L-proline with N,O-dimethylhydroxylamine They discovered that 2-acetyl-1-pyrroline can be suitably produced by using the reaction product obtained by the method, and have completed the present invention.
すなわち、本願第一の発明は、
“Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリンとＮ,O-ジメチルヒドロキシルアミンとの反応工程を含む2-アセチル-1-ピロリンの製造方法。”、である。 That is, the first invention of the present application is
"A method for producing 2-acetyl-1-pyrroline comprising a reaction step of N-(tert-butoxycarbonyl)-L-proline and N,O-dimethylhydroxylamine."
“Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリンとＮ,O-ジメチルヒドロキシルアミンとの反応工程を含む2-アセチル-1-ピロリンの製造方法。”、である。 That is, the first invention of the present application is
"A method for producing 2-acetyl-1-pyrroline comprising a reaction step of N-(tert-butoxycarbonyl)-L-proline and N,O-dimethylhydroxylamine."
次に、前記の反応は、Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリンと、1,1-カルボニルジイミダゾール及びN,O-ジメチルヒドロキシルアミン塩酸塩により行うことが好ましい。
すなわち、本願第二の発明は、
“前記反応工程をＮ-(tert-ブトキシカルボニル)-Ｌ-プロリンと、1,1-カルボニルジイミダゾール及びN,O-ジメチルヒドロキシルアミン塩酸塩との反応工程により行う請求項１に記載の2-アセチル-1-ピロリンを製造方法。”、である。 Next, the above reaction is preferably carried out using N-(tert-butoxycarbonyl)-L-proline, 1,1-carbonyldiimidazole and N,O-dimethylhydroxylamine hydrochloride.
That is, the second invention of the present application is
2- according to claim 1, wherein the reaction step is carried out by a reaction step of N-(tert-butoxycarbonyl)-L-proline, 1,1-carbonyldiimidazole and N,O-dimethylhydroxylamine hydrochloride. "Method for producing acetyl-1-pyrroline."
すなわち、本願第二の発明は、
“前記反応工程をＮ-(tert-ブトキシカルボニル)-Ｌ-プロリンと、1,1-カルボニルジイミダゾール及びN,O-ジメチルヒドロキシルアミン塩酸塩との反応工程により行う請求項１に記載の2-アセチル-1-ピロリンを製造方法。”、である。 Next, the above reaction is preferably carried out using N-(tert-butoxycarbonyl)-L-proline, 1,1-carbonyldiimidazole and N,O-dimethylhydroxylamine hydrochloride.
That is, the second invention of the present application is
2- according to claim 1, wherein the reaction step is carried out by a reaction step of N-(tert-butoxycarbonyl)-L-proline, 1,1-carbonyldiimidazole and N,O-dimethylhydroxylamine hydrochloride. "Method for producing acetyl-1-pyrroline."
次に、上記Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリンとN,O-ジメチルヒドロキシルアミンとの反応後において、グリニャール反応によってＮ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジンを得ることが好ましい。
すなわち、本願第三の発明は、
“前記Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリンとN,O-ジメチルヒドロキシルアミンとの反応工程後において、グリニャール反応によってＮ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジンを得る反応工程を含む、請求項１又は２に記載の2-アセチル-1-ピロリンの製造方法。”、である。 Next, after the reaction of the above N-(tert-butoxycarbonyl)-L-proline and N,O-dimethylhydroxylamine, N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine is obtained by a Grignard reaction. is preferred.
That is, the third invention of the present application is
“A reaction step for obtaining N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine by a Grignard reaction after the reaction step of the N-(tert-butoxycarbonyl)-L-proline and N,O-dimethylhydroxylamine. The method for producing 2-acetyl-1-pyrroline according to claim 1 or 2, which comprises:
すなわち、本願第三の発明は、
“前記Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリンとN,O-ジメチルヒドロキシルアミンとの反応工程後において、グリニャール反応によってＮ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジンを得る反応工程を含む、請求項１又は２に記載の2-アセチル-1-ピロリンの製造方法。”、である。 Next, after the reaction of the above N-(tert-butoxycarbonyl)-L-proline and N,O-dimethylhydroxylamine, N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine is obtained by a Grignard reaction. is preferred.
That is, the third invention of the present application is
“A reaction step for obtaining N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine by a Grignard reaction after the reaction step of the N-(tert-butoxycarbonyl)-L-proline and N,O-dimethylhydroxylamine. The method for producing 2-acetyl-1-pyrroline according to claim 1 or 2, which comprises:
次に、上記グリニャール反応は、メチルマグネシウムブロマイドにより行うことが好適である。
すなわち、本願第四の発明は、
“前記グリニャール反応をメチルマグネシウムブロマイドとの反応工程により行う請求項３に記載の2-アセチル-1-ピロリンの製造方法。”、である。 Next, the Grignard reaction is preferably carried out using methylmagnesium bromide.
That is, the fourth invention of the present application is
"The method for producing 2-acetyl-1-pyrroline according to claim 3, wherein the Grignard reaction is carried out by a reaction step with methylmagnesium bromide."
すなわち、本願第四の発明は、
“前記グリニャール反応をメチルマグネシウムブロマイドとの反応工程により行う請求項３に記載の2-アセチル-1-ピロリンの製造方法。”、である。 Next, the Grignard reaction is preferably carried out using methylmagnesium bromide.
That is, the fourth invention of the present application is
"The method for producing 2-acetyl-1-pyrroline according to claim 3, wherein the Grignard reaction is carried out by a reaction step with methylmagnesium bromide."
次に、Ｎ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジンについては、脱保護及び酸化によって2-アセチル-1-ピロリンを得ることが好ましい。
すなわち、本願第五の発明は、
“前記Ｎ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジンについて脱保護及び酸化によって、2-アセチル-1-ピロリンを得る反応工程を含む請求項３又は４に記載の2-アセチル-1-ピロリンの製造方法。”、である。 Next, for N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine, it is preferable to obtain 2-acetyl-1-pyrrolidine by deprotection and oxidation.
That is, the fifth invention of the present application is
“2-acetyl-1-pyrrolidine according to claim 3 or 4, comprising a reaction step of obtaining 2-acetyl-1-pyrroline by deprotecting and oxidizing the N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine. ``Method for producing pyrroline.''
すなわち、本願第五の発明は、
“前記Ｎ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジンについて脱保護及び酸化によって、2-アセチル-1-ピロリンを得る反応工程を含む請求項３又は４に記載の2-アセチル-1-ピロリンの製造方法。”、である。 Next, for N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine, it is preferable to obtain 2-acetyl-1-pyrrolidine by deprotection and oxidation.
That is, the fifth invention of the present application is
“2-acetyl-1-pyrrolidine according to claim 3 or 4, comprising a reaction step of obtaining 2-acetyl-1-pyrroline by deprotecting and oxidizing the N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine. ``Method for producing pyrroline.''
次に、本発明は上記の一連の製造ステップによることが可能である。
すなわち、本願第六の発明は、
“次の工程（Ａ）～（Ｄ）を含む2-アセチル-1-ピロリンの製造方法。
・工程（Ａ）：Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリンをアミド化して、Ｎ-メチル-Ｎ-(Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリル)-O-メチルヒドロキルアミンを得る工程
・工程（Ｂ）：Ｎ-メチル-Ｎ-(Ｎ-(tert-ブトキシカルボニル)-L-プロリル)-O-メチルヒドロキルアミンをグリニャール反応によりＮ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジンを得る工程
・工程（Ｃ）：Ｎ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジンの脱保護基を行い2-アセチル-ピロリジンを得る工程。
・工程（Ｄ）:2-アセチル-ピロリジンを酸化して2-アセチル-1-ピロリンを得る工程“、である。
The invention can then depend on the series of manufacturing steps described above.
That is, the sixth invention of the present application is:
“A method for producing 2-acetyl-1-pyrroline comprising the following steps (A) to (D).
・Step (A): N-(tert-butoxycarbonyl)-L-proline is amidated to produce N-methyl-N-(N-(tert-butoxycarbonyl)-L-prolyl)-O-methylhydrokylamine. Obtaining step/step (B): N-methyl-N-(N-(tert-butoxycarbonyl)-L-prolyl)-O-methylhydrokylamine is subjected to Grignard reaction to obtain N-(tert-butoxycarbonyl)-2-acetyl -Process of obtaining pyrrolidine/Step (C): A step of deprotecting N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine to obtain 2-acetyl-pyrrolidine.
- Step (D): oxidizing 2-acetyl-pyrrolidine to obtain 2-acetyl-1-pyrroline.
すなわち、本願第六の発明は、
“次の工程（Ａ）～（Ｄ）を含む2-アセチル-1-ピロリンの製造方法。
・工程（Ａ）：Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリンをアミド化して、Ｎ-メチル-Ｎ-(Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリル)-O-メチルヒドロキルアミンを得る工程
・工程（Ｂ）：Ｎ-メチル-Ｎ-(Ｎ-(tert-ブトキシカルボニル)-L-プロリル)-O-メチルヒドロキルアミンをグリニャール反応によりＮ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジンを得る工程
・工程（Ｃ）：Ｎ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジンの脱保護基を行い2-アセチル-ピロリジンを得る工程。
・工程（Ｄ）:2-アセチル-ピロリジンを酸化して2-アセチル-1-ピロリンを得る工程“、である。
The invention can then depend on the series of manufacturing steps described above.
That is, the sixth invention of the present application is:
“A method for producing 2-acetyl-1-pyrroline comprising the following steps (A) to (D).
・Step (A): N-(tert-butoxycarbonyl)-L-proline is amidated to produce N-methyl-N-(N-(tert-butoxycarbonyl)-L-prolyl)-O-methylhydrokylamine. Obtaining step/step (B): N-methyl-N-(N-(tert-butoxycarbonyl)-L-prolyl)-O-methylhydrokylamine is subjected to Grignard reaction to obtain N-(tert-butoxycarbonyl)-2-acetyl -Process of obtaining pyrrolidine/Step (C): A step of deprotecting N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine to obtain 2-acetyl-pyrrolidine.
- Step (D): oxidizing 2-acetyl-pyrrolidine to obtain 2-acetyl-1-pyrroline.
本発明の製造方法よって、2-アセチル-1-ピロリンを極低温条件や高圧条件を必要とすることなく簡便に製造することができる。これによって食品産業を含み、種々の産業分野において、2-アセチル-1-ピロリンを提供することができる。
According to the production method of the present invention, 2-acetyl-1-pyrroline can be easily produced without requiring cryogenic conditions or high pressure conditions. This makes it possible to provide 2-acetyl-1-pyrroline in various industrial fields, including the food industry.
According to the production method of the present invention, 2-acetyl-1-pyrroline can be easily produced without requiring cryogenic conditions or high pressure conditions. This makes it possible to provide 2-acetyl-1-pyrroline in various industrial fields, including the food industry.
以下、本発明を詳細に説明する。
本発明の2-アセチル-1-ピロリンの製造方法は、例えば図１に記載する各工程を経る製造方法が例示される。尚、上記各工程においては、化合物１～５は以下を示す。 The present invention will be explained in detail below.
An example of the method for producing 2-acetyl-1-pyrroline of the present invention is a method that involves the steps shown in FIG. 1, for example. In addition, in each of the above steps, compounds 1 to 5 are as follows.
本発明の2-アセチル-1-ピロリンの製造方法は、例えば図１に記載する各工程を経る製造方法が例示される。尚、上記各工程においては、化合物１～５は以下を示す。 The present invention will be explained in detail below.
An example of the method for producing 2-acetyl-1-pyrroline of the present invention is a method that involves the steps shown in FIG. 1, for example. In addition, in each of the above steps, compounds 1 to 5 are as follows.
化合物１：Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリン
Ｎ-(tert-butoxycarbonyl)-Ｌ-proline
別名 ：2-[(2-メチルプロパン-2-イル)オキシカルボニル] シクロペンタン-1-カルボン酸
2-[(2-methylpropan-2-yl)oxycarbonyl]cyclopentane-1-carboxylic acid
化合物２：Ｎ-メチル-Ｎ-[Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリル)]-O-メチルヒドロキルアミン
N-methyl-N-(N-(tert-butoxycarbonyl)-L-prolyl)-O-methylhydroxylamine
別名 ：tert-ブチル-2-[メトキシ (メチル)カルバモイル]ピロリジン-1-カルボキシレート
tert-butyl 2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate
化合物３：Ｎ-(tert-ブトキシカルボニル)-2-アセチルピロリジン
Ｎ-(tert- butoxycarbonyl)-2- acetylpyrrolidine
別名 ：tert-ブチル 2-アセチルピロリジン-1-カルボキシレート
tert-butyl 2-acetylpyrrolidine-1-carboxylate
化合物４：2-アセチル-ピロリジン
2-acetylpyrrolidine
別名 ：1-(ピロリジン-2-イル)エタノン
1-(pyrrolidin-2-yl)ethanone
化合物５：2-アセチル-1-ピロリン
2-acetyl-1-pyrroline
別名 ：1-(3,4-ジヒドロ-2H-ピロール-5-イル)エタノン
1-(3,4-dihydro-2H-pyrrol-5-yl)ethenone
Compound 1: N-(tert-butoxycarbonyl)-L-proline
Other name: 2-[(2-methylpropan-2-yl)oxycarbonyl]cyclopentane-1-carboxylic acid
Compound 2: N-methyl-N-[N-(tert-butoxycarbonyl)-L-prolyl)]-O-methylhydrokylamine
N-methyl-N-(N-(tert-butoxycarbonyl)-L-prolyl)-O-methylhydroxylamine
Other name: tert-butyl-2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate
tert-butyl 2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate
Compound 3: N-(tert-butoxycarbonyl)-2-acetylpyrrolidine
Other name: tert-butyl 2-acetylpyrrolidine-1-carboxylate
Compound 4: 2-acetylpyrrolidine
Other name: 1-(pyrrolidin-2-yl)ethanone
Compound 5: 2-acetyl-1-pyrroline
Other name: 1-(3,4-dihydro-2H-pyrrol-5-yl)ethanone
Ｎ-(tert-butoxycarbonyl)-Ｌ-proline
別名 ：2-[(2-メチルプロパン-2-イル)オキシカルボニル] シクロペンタン-1-カルボン酸
2-[(2-methylpropan-2-yl)oxycarbonyl]cyclopentane-1-carboxylic acid
化合物２：Ｎ-メチル-Ｎ-[Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリル)]-O-メチルヒドロキルアミン
N-methyl-N-(N-(tert-butoxycarbonyl)-L-prolyl)-O-methylhydroxylamine
別名 ：tert-ブチル-2-[メトキシ (メチル)カルバモイル]ピロリジン-1-カルボキシレート
tert-butyl 2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate
化合物３：Ｎ-(tert-ブトキシカルボニル)-2-アセチルピロリジン
Ｎ-(tert- butoxycarbonyl)-2- acetylpyrrolidine
別名 ：tert-ブチル 2-アセチルピロリジン-1-カルボキシレート
tert-butyl 2-acetylpyrrolidine-1-carboxylate
化合物４：2-アセチル-ピロリジン
2-acetylpyrrolidine
別名 ：1-(ピロリジン-2-イル)エタノン
1-(pyrrolidin-2-yl)ethanone
化合物５：2-アセチル-1-ピロリン
2-acetyl-1-pyrroline
別名 ：1-(3,4-ジヒドロ-2H-ピロール-5-イル)エタノン
1-(3,4-dihydro-2H-pyrrol-5-yl)ethenone
Compound 1: N-(tert-butoxycarbonyl)-L-proline
Other name: 2-[(2-methylpropan-2-yl)oxycarbonyl]cyclopentane-1-carboxylic acid
Compound 2: N-methyl-N-[N-(tert-butoxycarbonyl)-L-prolyl)]-O-methylhydrokylamine
N-methyl-N-(N-(tert-butoxycarbonyl)-L-prolyl)-O-methylhydroxylamine
Other name: tert-butyl-2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate
tert-butyl 2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate
Compound 3: N-(tert-butoxycarbonyl)-2-acetylpyrrolidine
Other name: tert-butyl 2-acetylpyrrolidine-1-carboxylate
Compound 4: 2-acetylpyrrolidine
Other name: 1-(pyrrolidin-2-yl)ethanone
Compound 5: 2-acetyl-1-pyrroline
Other name: 1-(3,4-dihydro-2H-pyrrol-5-yl)ethanone
以下、各工程について説明する。
・第一工程（アミド化反応）
本工程は、化合物１：BOC-Ｌ-プロリンに対してこれを、アミド化する工程である。本願発明は、本ステップを特徴とする。Ｌ-プロリンに保護基であるtert-ブトキシカルボニル保護基を結合した状態でＬ-プロリンのカルボキシル基とN,O-ジメチルヒドロキシルアミンを反応させてアミドを形成させる。 Each step will be explained below.
・First step (amidation reaction)
This step is a step of amidating compound 1: BOC-L-proline. The present invention is characterized by this step. With L-proline bound to a tert-butoxycarbonyl protecting group, the carboxyl group of L-proline is reacted with N,O-dimethylhydroxylamine to form an amide.
・第一工程（アミド化反応）
本工程は、化合物１：BOC-Ｌ-プロリンに対してこれを、アミド化する工程である。本願発明は、本ステップを特徴とする。Ｌ-プロリンに保護基であるtert-ブトキシカルボニル保護基を結合した状態でＬ-プロリンのカルボキシル基とN,O-ジメチルヒドロキシルアミンを反応させてアミドを形成させる。 Each step will be explained below.
・First step (amidation reaction)
This step is a step of amidating compound 1: BOC-L-proline. The present invention is characterized by this step. With L-proline bound to a tert-butoxycarbonyl protecting group, the carboxyl group of L-proline is reacted with N,O-dimethylhydroxylamine to form an amide.
尚、BOC-プロリンについては、Ｌ-プロリン出発原料として二炭酸ジ-tert-ブチル（Boc2O）等によって処理することによって製造することも勿論可能である。
また、本アミド化においては、カルボキシイミダゾールや塩化チオニル等を利用して、BOC- Ｌ-プロリンのカルボキシ基についてアシル基をアミンに移動させることができる。尚、アミンには、N,O-ジメチルヒドロキルアミンを利用する。
また、カルボキシイミダゾールの場合は室温、塩化チオニルの場合には５～１０℃程度で実施することが好ましい。尚、N,O-ジメチルヒドロキシルアミンのアミドのことを、ワインレブアミド (Weinreb amide) と称する場合もある。 It is of course possible to produce BOC-proline by treating it with di-tert-butyl dicarbonate (Boc2O) or the like as a starting material for L-proline.
Furthermore, in this amidation, the acyl group of the carboxy group of BOC-L-proline can be transferred to the amine using carboxyimidazole, thionyl chloride, or the like. Note that N,O-dimethylhydrokylamine is used as the amine.
Further, in the case of carboxyimidazole, it is preferable to carry out the reaction at room temperature, and in the case of thionyl chloride, it is preferable to carry out the reaction at about 5 to 10°C. Note that the amide of N,O-dimethylhydroxylamine is sometimes referred to as Weinreb amide.
また、本アミド化においては、カルボキシイミダゾールや塩化チオニル等を利用して、BOC- Ｌ-プロリンのカルボキシ基についてアシル基をアミンに移動させることができる。尚、アミンには、N,O-ジメチルヒドロキルアミンを利用する。
また、カルボキシイミダゾールの場合は室温、塩化チオニルの場合には５～１０℃程度で実施することが好ましい。尚、N,O-ジメチルヒドロキシルアミンのアミドのことを、ワインレブアミド (Weinreb amide) と称する場合もある。 It is of course possible to produce BOC-proline by treating it with di-tert-butyl dicarbonate (Boc2O) or the like as a starting material for L-proline.
Furthermore, in this amidation, the acyl group of the carboxy group of BOC-L-proline can be transferred to the amine using carboxyimidazole, thionyl chloride, or the like. Note that N,O-dimethylhydrokylamine is used as the amine.
Further, in the case of carboxyimidazole, it is preferable to carry out the reaction at room temperature, and in the case of thionyl chloride, it is preferable to carry out the reaction at about 5 to 10°C. Note that the amide of N,O-dimethylhydroxylamine is sometimes referred to as Weinreb amide.
具体的な例として、Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリンをN,O-ジメチルヒドロキルアミンと反応させて、化合物２（Ｎ-メチル-Ｎ-(Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリル)-O-メチルヒドロキルアミン）を調製する方法が挙げられる。
尚、基質当量については、概ねBOCプロリンを1とした時、カルボキシイミダゾールおよびN,O-ジメチルヒドロキルアミンは1.2当量程度とすることが好適である。 As a specific example, N-(tert-butoxycarbonyl)-L-proline is reacted with N,O-dimethylhydrokylamine to form compound 2 (N-methyl-N-(N-(tert-butoxycarbonyl)- (L-prolyl)-O-methylhydrokylamine).
Regarding the substrate equivalent, when BOC proline is approximately 1, it is preferable that carboxyimidazole and N,O-dimethylhydrokylamine be approximately 1.2 equivalents.
尚、基質当量については、概ねBOCプロリンを1とした時、カルボキシイミダゾールおよびN,O-ジメチルヒドロキルアミンは1.2当量程度とすることが好適である。 As a specific example, N-(tert-butoxycarbonyl)-L-proline is reacted with N,O-dimethylhydrokylamine to form compound 2 (N-methyl-N-(N-(tert-butoxycarbonyl)- (L-prolyl)-O-methylhydrokylamine).
Regarding the substrate equivalent, when BOC proline is approximately 1, it is preferable that carboxyimidazole and N,O-dimethylhydrokylamine be approximately 1.2 equivalents.
・第二工程（Grignard反応）
本工程は、第一工程で得られた化合物２（Ｎ-メチル-Ｎ-(Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリル)-O-メチルヒドロキルアミン）に対して、グリニャール反応において当該化合物２とグリニャール試薬を反応させることによってアミドを分解させてケトンを製造するステップである。 ・Second step (Grignard reaction)
In this step, the compound 2 (N-methyl-N-(N-(tert-butoxycarbonyl)-L-prolyl)-O-methylhydrokylamine) obtained in the first step is subjected to a Grignard reaction. In this step, the amide is decomposed by reacting 2 with a Grignard reagent to produce a ketone.
本工程は、第一工程で得られた化合物２（Ｎ-メチル-Ｎ-(Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリル)-O-メチルヒドロキルアミン）に対して、グリニャール反応において当該化合物２とグリニャール試薬を反応させることによってアミドを分解させてケトンを製造するステップである。 ・Second step (Grignard reaction)
In this step, the compound 2 (N-methyl-N-(N-(tert-butoxycarbonyl)-L-prolyl)-O-methylhydrokylamine) obtained in the first step is subjected to a Grignard reaction. In this step, the amide is decomposed by reacting 2 with a Grignard reagent to produce a ketone.
尚、この反応においては、通常生じたケトンが再度グリニャール試薬と反応することによってアルコールが生成する副反応を抑えることができる。
具体的には、グリニャール反応においては、グリニャール試薬をハロゲン化したメチルと金属マグネシウムから調製しておき、当該グリニャール試薬を第一工程で得られた化合物２（Ｎ-メチル-Ｎ-(Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリル)-O-メチルヒドロキルアミン）に添加する。添加の方法としては、グリニャール試薬を第一工程で得られた化合物に滴下する方法が挙げられる。 In addition, in this reaction, the side reaction in which alcohol is produced can be suppressed by reacting the ketone produced again with the Grignard reagent.
Specifically, in the Grignard reaction, a Grignard reagent is prepared from halogenated methyl and metallic magnesium, and the Grignard reagent is converted into compound 2 (N-methyl-N-(N-( tert-butoxycarbonyl)-L-prolyl)-O-methylhydrokylamine). Examples of the addition method include a method of dropping a Grignard reagent onto the compound obtained in the first step.
具体的には、グリニャール反応においては、グリニャール試薬をハロゲン化したメチルと金属マグネシウムから調製しておき、当該グリニャール試薬を第一工程で得られた化合物２（Ｎ-メチル-Ｎ-(Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリル)-O-メチルヒドロキルアミン）に添加する。添加の方法としては、グリニャール試薬を第一工程で得られた化合物に滴下する方法が挙げられる。 In addition, in this reaction, the side reaction in which alcohol is produced can be suppressed by reacting the ketone produced again with the Grignard reagent.
Specifically, in the Grignard reaction, a Grignard reagent is prepared from halogenated methyl and metallic magnesium, and the Grignard reagent is converted into compound 2 (N-methyl-N-(N-( tert-butoxycarbonyl)-L-prolyl)-O-methylhydrokylamine). Examples of the addition method include a method of dropping a Grignard reagent onto the compound obtained in the first step.
具体的な例として、第一工程で得られ化合物２（Ｎ-メチル-Ｎ-(Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリル)-O-メチルヒドロキルアミン）に対してメチルマグネシウムブロマイドやメチルマグネシウムクロライドを反応させる方法が挙げられる。これによってアミドを分解させて、化合物３（Ｎ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジン）を調製することができる。
As a specific example, methylmagnesium bromide or methyl One example is a method of reacting magnesium chloride. This allows the amide to be decomposed to prepare compound 3 (N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine).
尚、前記のメチルマグネシウムブロマイドに代えてエチルマグネシウムブロマイドを利用することによってN-(tert-ブトキシカルボニル)-2-プロピオニル-ピロリジンとすることもでき、これから2-プロピオニル-1-ピロリンを製造することもできる。
このように本発明を応用することで2-アセチル-1-ピロリンの類縁化合物の合成を可能とすることができる。尚、基質当量としては、概ね化合物2（（Ｎ-メチル-Ｎ-(Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリル)-O-メチルヒドロキルアミン）を1とした時、メチルマグネシウムブロマイドは2.1当量程度とすることが好ましい。 In addition, by using ethylmagnesium bromide in place of the above-mentioned methylmagnesium bromide, N-(tert-butoxycarbonyl)-2-propionyl-pyrrolidine can be obtained, and 2-propionyl-1-pyrrolidine can be produced from this. You can also do it.
By applying the present invention in this way, it is possible to synthesize analogous compounds of 2-acetyl-1-pyrroline. The substrate equivalent weight is approximately 1 for compound 2 ((N-methyl-N-(N-(tert-butoxycarbonyl)-L-prolyl)-O-methylhydrokylamine) and 2.1 for methylmagnesium bromide. It is preferable to use about an equivalent amount.
このように本発明を応用することで2-アセチル-1-ピロリンの類縁化合物の合成を可能とすることができる。尚、基質当量としては、概ね化合物2（（Ｎ-メチル-Ｎ-(Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリル)-O-メチルヒドロキルアミン）を1とした時、メチルマグネシウムブロマイドは2.1当量程度とすることが好ましい。 In addition, by using ethylmagnesium bromide in place of the above-mentioned methylmagnesium bromide, N-(tert-butoxycarbonyl)-2-propionyl-pyrrolidine can be obtained, and 2-propionyl-1-pyrrolidine can be produced from this. You can also do it.
By applying the present invention in this way, it is possible to synthesize analogous compounds of 2-acetyl-1-pyrroline. The substrate equivalent weight is approximately 1 for compound 2 ((N-methyl-N-(N-(tert-butoxycarbonyl)-L-prolyl)-O-methylhydrokylamine) and 2.1 for methylmagnesium bromide. It is preferable to use about an equivalent amount.
・第三工程（脱保護反応）
次に、第二工程で得られたピロリジンの窒素の保護基であるＮ-(tert-ブトキシカルボニル)について脱保護を行う。脱保護はトリフルオロ酢酸や、塩酸を加える方法や、塩化水素／酢酸エチル溶液や塩化水素／ジオキサン溶液、塩化水素／シクロペンチルメチルエーテル溶液等を利用することができる。
具体的な例として、化合物３(Ｎ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジン)に対して、トリフルオロ酢酸を滴下等することによって脱保護反応を行い、2-アセチル-ピロリジンを調製する方法が挙げられる。 ・Third step (deprotection reaction)
Next, N-(tert-butoxycarbonyl), which is the nitrogen protecting group of the pyrrolidine obtained in the second step, is deprotected. For deprotection, a method of adding trifluoroacetic acid or hydrochloric acid, a hydrogen chloride/ethyl acetate solution, a hydrogen chloride/dioxane solution, a hydrogen chloride/cyclopentyl methyl ether solution, etc. can be used.
As a specific example, compound 3 (N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine) is subjected to a deprotection reaction by dropping trifluoroacetic acid to prepare 2-acetyl-pyrrolidine. One method is to do so.
次に、第二工程で得られたピロリジンの窒素の保護基であるＮ-(tert-ブトキシカルボニル)について脱保護を行う。脱保護はトリフルオロ酢酸や、塩酸を加える方法や、塩化水素／酢酸エチル溶液や塩化水素／ジオキサン溶液、塩化水素／シクロペンチルメチルエーテル溶液等を利用することができる。
具体的な例として、化合物３(Ｎ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジン)に対して、トリフルオロ酢酸を滴下等することによって脱保護反応を行い、2-アセチル-ピロリジンを調製する方法が挙げられる。 ・Third step (deprotection reaction)
Next, N-(tert-butoxycarbonyl), which is the nitrogen protecting group of the pyrrolidine obtained in the second step, is deprotected. For deprotection, a method of adding trifluoroacetic acid or hydrochloric acid, a hydrogen chloride/ethyl acetate solution, a hydrogen chloride/dioxane solution, a hydrogen chloride/cyclopentyl methyl ether solution, etc. can be used.
As a specific example, compound 3 (N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine) is subjected to a deprotection reaction by dropping trifluoroacetic acid to prepare 2-acetyl-pyrrolidine. One method is to do so.
・第四工程（酸化反応）
第三工程で得られた2-アセチル-ピロリジンを酸化することによって2-アセチル-1-ピロリンを調製することができる。酸化の工程については種々の方法を選択することができるが、例えば、酸素を酸化剤として使用することが可能である。
さらに、別の方法として、クロム酸酸化、TEMPO酸化、Dess-Martin酸化、Oppenauer酸化等が挙げられる
・Fourth step (oxidation reaction)
2-acetyl-1-pyrroline can be prepared by oxidizing 2-acetyl-pyrrolidine obtained in the third step. Various methods can be selected for the oxidation step; for example, oxygen can be used as the oxidizing agent.
Additionally, other methods include chromic acid oxidation, TEMPO oxidation, Dess-Martin oxidation, Oppenauer oxidation, etc.
第三工程で得られた2-アセチル-ピロリジンを酸化することによって2-アセチル-1-ピロリンを調製することができる。酸化の工程については種々の方法を選択することができるが、例えば、酸素を酸化剤として使用することが可能である。
さらに、別の方法として、クロム酸酸化、TEMPO酸化、Dess-Martin酸化、Oppenauer酸化等が挙げられる
・Fourth step (oxidation reaction)
2-acetyl-1-pyrroline can be prepared by oxidizing 2-acetyl-pyrrolidine obtained in the third step. Various methods can be selected for the oxidation step; for example, oxygen can be used as the oxidizing agent.
Additionally, other methods include chromic acid oxidation, TEMPO oxidation, Dess-Martin oxidation, Oppenauer oxidation, etc.
以下、本発明について実施例を用いて説明する。本発明はこれらの実施例に限定されるものではない。
Hereinafter, the present invention will be explained using examples. The present invention is not limited to these examples.
[実施例１]2-アセチル-1-ピロリンの製造方法
─第一工程─（BOCプロリンのアミド化）
窒素雰囲気下、化合物１（BOCプロリン）（20ｇ）をジクロロメタン（160ml）に溶解し、撹拌しながら1,1-カルボキシイミダゾール（18.1g）を添加し、室温下一時間攪拌を継続した。その後N,O-ジヒドロキシルアミン塩酸塩(10.9ｇ)を攪拌中の反応液に添加し、さらに三時間攪拌を継続した。GCにて反応の終了を確認したのち、蒸留水を（240ml）を室温下で滴下ししばらく攪拌した。反応液を分液し、得られた有機層に1％希塩酸（60ml）及び蒸留水（80ml）を用いて洗浄および分液し、有機層を得た。得られた有機層を硫酸ナトリウムで乾燥後、濃縮し、化合物２（Ｎ-メチル-Ｎ-(Ｎ-(tert-ブトキシカルボニル)-L-プロリル)-O-メチルヒドロキルアミン）（21.0g,87.5%）を得た。図２に第一工程を示す。 [Example 1] Method for producing 2-acetyl-1-pyrroline - First step - (Amidation of BOC proline)
Compound 1 (BOC proline) (20 g) was dissolved in dichloromethane (160 ml) under a nitrogen atmosphere, 1,1-carboximidazole (18.1 g) was added with stirring, and stirring was continued for one hour at room temperature. Thereafter, N,O-dihydroxylamine hydrochloride (10.9 g) was added to the stirring reaction solution, and stirring was continued for an additional 3 hours. After confirming the completion of the reaction by GC, distilled water (240 ml) was added dropwise at room temperature and stirred for a while. The reaction solution was separated, and the resulting organic layer was washed and separated using 1% diluted hydrochloric acid (60 ml) and distilled water (80 ml) to obtain an organic layer. The obtained organic layer was dried over sodium sulfate and then concentrated to give compound 2 (N-methyl-N-(N-(tert-butoxycarbonyl)-L-prolyl)-O-methylhydrokylamine) (21.0 g, 87.5 %) was obtained. Figure 2 shows the first step.
─第一工程─（BOCプロリンのアミド化）
窒素雰囲気下、化合物１（BOCプロリン）（20ｇ）をジクロロメタン（160ml）に溶解し、撹拌しながら1,1-カルボキシイミダゾール（18.1g）を添加し、室温下一時間攪拌を継続した。その後N,O-ジヒドロキシルアミン塩酸塩(10.9ｇ)を攪拌中の反応液に添加し、さらに三時間攪拌を継続した。GCにて反応の終了を確認したのち、蒸留水を（240ml）を室温下で滴下ししばらく攪拌した。反応液を分液し、得られた有機層に1％希塩酸（60ml）及び蒸留水（80ml）を用いて洗浄および分液し、有機層を得た。得られた有機層を硫酸ナトリウムで乾燥後、濃縮し、化合物２（Ｎ-メチル-Ｎ-(Ｎ-(tert-ブトキシカルボニル)-L-プロリル)-O-メチルヒドロキルアミン）（21.0g,87.5%）を得た。図２に第一工程を示す。 [Example 1] Method for producing 2-acetyl-1-pyrroline - First step - (Amidation of BOC proline)
Compound 1 (BOC proline) (20 g) was dissolved in dichloromethane (160 ml) under a nitrogen atmosphere, 1,1-carboximidazole (18.1 g) was added with stirring, and stirring was continued for one hour at room temperature. Thereafter, N,O-dihydroxylamine hydrochloride (10.9 g) was added to the stirring reaction solution, and stirring was continued for an additional 3 hours. After confirming the completion of the reaction by GC, distilled water (240 ml) was added dropwise at room temperature and stirred for a while. The reaction solution was separated, and the resulting organic layer was washed and separated using 1% diluted hydrochloric acid (60 ml) and distilled water (80 ml) to obtain an organic layer. The obtained organic layer was dried over sodium sulfate and then concentrated to give compound 2 (N-methyl-N-(N-(tert-butoxycarbonyl)-L-prolyl)-O-methylhydrokylamine) (21.0 g, 87.5 %) was obtained. Figure 2 shows the first step.
─第二工程─（Grignard反応）
窒素雰囲気下、化合物２（Ｎ-メチル-Ｎ-(Ｎ-(tert-ブトキシカルボニル)-L-プロリル)-O-メチルヒドロキルアミン）（20ｇ）を乾燥ジエチルエーテル（120ml）に溶解し、反応液を－10℃～0℃まで冷却し、撹拌した。3.0Ｍのメチルマグネシウムブロマイドジエチルエーテル溶液（54.2ml）を－10℃から0℃の条件下で一時間かけて滴下した。滴下後、反応液を室温に戻しさらに一時間攪拌を継続した。GCにて反応の終了を確認したのち、飽和塩化ナトリウム水溶液240ml）を氷浴下にて滴下し、しばらく攪拌を継続した。反応液を分液し、得られた水層を酢酸エチルを用いて抽出を実施したのち、有機層を混合させ、飽和食塩水で洗浄後および分液後、有機層を得た。得られた有機層を硫酸ナトリウムで洗浄後及び分液後、有機層を得た。得られた有機層を硫酸ナトリウムで乾燥後、濃縮し、化合物３（Ｎ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジン）（14.3g,82.3%）を得た。図３に第二工程を示す。 ─Second step─ (Grignard reaction)
Under a nitrogen atmosphere, compound 2 (N-methyl-N-(N-(tert-butoxycarbonyl)-L-prolyl)-O-methylhydrokylamine) (20 g) was dissolved in dry diethyl ether (120 ml), and the reaction solution The mixture was cooled to -10°C to 0°C and stirred. A 3.0M methylmagnesium bromide diethyl ether solution (54.2 ml) was added dropwise at -10°C to 0°C over 1 hour. After the dropwise addition, the reaction solution was returned to room temperature and stirring was continued for another hour. After confirming the completion of the reaction by GC, 240 ml of a saturated aqueous sodium chloride solution was added dropwise in an ice bath, and stirring was continued for a while. The reaction solution was separated, and the resulting aqueous layer was extracted with ethyl acetate, and the organic layers were mixed. After washing with saturated brine and separation, an organic layer was obtained. After washing the obtained organic layer with sodium sulfate and separating the layers, an organic layer was obtained. The obtained organic layer was dried over sodium sulfate and then concentrated to obtain compound 3 (N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine) (14.3 g, 82.3%). FIG. 3 shows the second step.
窒素雰囲気下、化合物２（Ｎ-メチル-Ｎ-(Ｎ-(tert-ブトキシカルボニル)-L-プロリル)-O-メチルヒドロキルアミン）（20ｇ）を乾燥ジエチルエーテル（120ml）に溶解し、反応液を－10℃～0℃まで冷却し、撹拌した。3.0Ｍのメチルマグネシウムブロマイドジエチルエーテル溶液（54.2ml）を－10℃から0℃の条件下で一時間かけて滴下した。滴下後、反応液を室温に戻しさらに一時間攪拌を継続した。GCにて反応の終了を確認したのち、飽和塩化ナトリウム水溶液240ml）を氷浴下にて滴下し、しばらく攪拌を継続した。反応液を分液し、得られた水層を酢酸エチルを用いて抽出を実施したのち、有機層を混合させ、飽和食塩水で洗浄後および分液後、有機層を得た。得られた有機層を硫酸ナトリウムで洗浄後及び分液後、有機層を得た。得られた有機層を硫酸ナトリウムで乾燥後、濃縮し、化合物３（Ｎ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジン）（14.3g,82.3%）を得た。図３に第二工程を示す。 ─Second step─ (Grignard reaction)
Under a nitrogen atmosphere, compound 2 (N-methyl-N-(N-(tert-butoxycarbonyl)-L-prolyl)-O-methylhydrokylamine) (20 g) was dissolved in dry diethyl ether (120 ml), and the reaction solution The mixture was cooled to -10°C to 0°C and stirred. A 3.0M methylmagnesium bromide diethyl ether solution (54.2 ml) was added dropwise at -10°C to 0°C over 1 hour. After the dropwise addition, the reaction solution was returned to room temperature and stirring was continued for another hour. After confirming the completion of the reaction by GC, 240 ml of a saturated aqueous sodium chloride solution was added dropwise in an ice bath, and stirring was continued for a while. The reaction solution was separated, and the resulting aqueous layer was extracted with ethyl acetate, and the organic layers were mixed. After washing with saturated brine and separation, an organic layer was obtained. After washing the obtained organic layer with sodium sulfate and separating the layers, an organic layer was obtained. The obtained organic layer was dried over sodium sulfate and then concentrated to obtain compound 3 (N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine) (14.3 g, 82.3%). FIG. 3 shows the second step.
─第三工程及び第四工程─（脱保護～酸化）
窒素雰囲気下、化合物３（Ｎ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジン）（5g）をジクロロメタン（14ml）に溶解し、室温下攪拌した。トリフルオロ酢酸（16.6ml）を３０分かけて滴下しさらに一時間攪拌を継続した。TLCを用いて原料の消失を確認したのち、ジクロロメタンを留去し、化合物４（2-アセチル-ピロリジン）の反応クルードを得た。 ─Third and fourth steps─ (Deprotection to oxidation)
Compound 3 (N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine) (5 g) was dissolved in dichloromethane (14 ml) under a nitrogen atmosphere and stirred at room temperature. Trifluoroacetic acid (16.6 ml) was added dropwise over 30 minutes, and stirring was continued for an additional hour. After confirming the disappearance of the raw materials using TLC, dichloromethane was distilled off to obtain a reaction crude of compound 4 (2-acetyl-pyrrolidine).
窒素雰囲気下、化合物３（Ｎ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジン）（5g）をジクロロメタン（14ml）に溶解し、室温下攪拌した。トリフルオロ酢酸（16.6ml）を３０分かけて滴下しさらに一時間攪拌を継続した。TLCを用いて原料の消失を確認したのち、ジクロロメタンを留去し、化合物４（2-アセチル-ピロリジン）の反応クルードを得た。 ─Third and fourth steps─ (Deprotection to oxidation)
Compound 3 (N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine) (5 g) was dissolved in dichloromethane (14 ml) under a nitrogen atmosphere and stirred at room temperature. Trifluoroacetic acid (16.6 ml) was added dropwise over 30 minutes, and stirring was continued for an additional hour. After confirming the disappearance of the raw materials using TLC, dichloromethane was distilled off to obtain a reaction crude of compound 4 (2-acetyl-pyrrolidine).
得られた化合物４の反応クルードに、飽和炭酸水素ナトリウム水溶液を加え、反応液が中性になるように調製した。反応液を、酸素雰囲気化、一時間攪拌させた。
GCを用いて原料の消失を確認したのち、反応液を室温に戻し、反応液を、ジエチルエーテル（20ml）を用いて3回抽出を実施した。得られた有機層を、硫酸ナトリウムを用いて乾燥後、減圧下、氷浴を用いて反応液を濃縮した。この際における濃縮時点の化合物５（2-アセチル-1-ピロリン）のＧＣ純度は89％であった。 A saturated aqueous sodium hydrogen carbonate solution was added to the obtained reaction crude of Compound 4 so that the reaction solution became neutral. The reaction solution was placed in an oxygen atmosphere and stirred for 1 hour.
After confirming the disappearance of the raw materials using GC, the reaction solution was returned to room temperature, and the reaction solution was extracted three times using diethyl ether (20 ml). After drying the obtained organic layer using sodium sulfate, the reaction solution was concentrated using an ice bath under reduced pressure. At this time, the GC purity of Compound 5 (2-acetyl-1-pyrroline) at the time of concentration was 89%.
GCを用いて原料の消失を確認したのち、反応液を室温に戻し、反応液を、ジエチルエーテル（20ml）を用いて3回抽出を実施した。得られた有機層を、硫酸ナトリウムを用いて乾燥後、減圧下、氷浴を用いて反応液を濃縮した。この際における濃縮時点の化合物５（2-アセチル-1-ピロリン）のＧＣ純度は89％であった。 A saturated aqueous sodium hydrogen carbonate solution was added to the obtained reaction crude of Compound 4 so that the reaction solution became neutral. The reaction solution was placed in an oxygen atmosphere and stirred for 1 hour.
After confirming the disappearance of the raw materials using GC, the reaction solution was returned to room temperature, and the reaction solution was extracted three times using diethyl ether (20 ml). After drying the obtained organic layer using sodium sulfate, the reaction solution was concentrated using an ice bath under reduced pressure. At this time, the GC purity of Compound 5 (2-acetyl-1-pyrroline) at the time of concentration was 89%.
さらに、得られた濃縮物（1.8g）にエタノール（30ml）を添加し、このエタノール溶液を減圧蒸留した。蒸留物として、化合物５（2-アセチル-1-ピロリン）を含有するエタノール溶液が得られた。蒸留後の化合物５（2-アセチル-1-ピロリン）のエタノール溶液には化合物５（2-アセチル-1-ピロリン）以外の成分は見受けられなかった。
また、減圧蒸留条件としては、化合物５（2-アセチル-1-ピロリン）のエタノール溶液を室温で大気圧から400torrまで減圧し、続いて室温から40℃まで徐々に加熱し留分を得た。さらに40℃から60℃まで徐々に加熱し留分を得た。図４に本第三工程及び第四工程を示す。 Furthermore, ethanol (30 ml) was added to the obtained concentrate (1.8 g), and this ethanol solution was distilled under reduced pressure. An ethanol solution containing compound 5 (2-acetyl-1-pyrroline) was obtained as a distillate. No components other than Compound 5 (2-acetyl-1-pyrroline) were found in the ethanol solution of Compound 5 (2-acetyl-1-pyrroline) after distillation.
Further, as the vacuum distillation conditions, an ethanol solution of Compound 5 (2-acetyl-1-pyrroline) was reduced from atmospheric pressure to 400 torr at room temperature, and then gradually heated from room temperature to 40°C to obtain a fraction. Further, the mixture was gradually heated from 40°C to 60°C to obtain a fraction. FIG. 4 shows the third and fourth steps.
また、減圧蒸留条件としては、化合物５（2-アセチル-1-ピロリン）のエタノール溶液を室温で大気圧から400torrまで減圧し、続いて室温から40℃まで徐々に加熱し留分を得た。さらに40℃から60℃まで徐々に加熱し留分を得た。図４に本第三工程及び第四工程を示す。 Furthermore, ethanol (30 ml) was added to the obtained concentrate (1.8 g), and this ethanol solution was distilled under reduced pressure. An ethanol solution containing compound 5 (2-acetyl-1-pyrroline) was obtained as a distillate. No components other than Compound 5 (2-acetyl-1-pyrroline) were found in the ethanol solution of Compound 5 (2-acetyl-1-pyrroline) after distillation.
Further, as the vacuum distillation conditions, an ethanol solution of Compound 5 (2-acetyl-1-pyrroline) was reduced from atmospheric pressure to 400 torr at room temperature, and then gradually heated from room temperature to 40°C to obtain a fraction. Further, the mixture was gradually heated from 40°C to 60°C to obtain a fraction. FIG. 4 shows the third and fourth steps.
また、ここで得られた2-アセチル-1-ピロリンのマススペクトル及びGCの保持指標は、構造既知の2-アセチル-1-ピロリンのものと完全に一致した。
Additionally, the mass spectrum and GC retention index of 2-acetyl-1-pyrroline obtained here completely matched those of 2-acetyl-1-pyrroline, whose structure is known.
本出願は、２０２２年３月１８日出願の日本出願・出願番号2022-043475に基づくものであり、その内容はここに参照として取り込まれる。
This application is based on the Japanese application, application number 2022-043475, filed on March 18, 2022, the contents of which are incorporated herein by reference.
Claims (6)
- Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリンとN,O-ジメチルヒドロキシルアミンとの反応工程を含む2-アセチル-1-ピロリンの製造方法。
A method for producing 2-acetyl-1-pyrroline, which includes a reaction step of N-(tert-butoxycarbonyl)-L-proline and N,O-dimethylhydroxylamine.
- 前記反応工程をＮ-(tert-ブトキシカルボニル)-Ｌ-プロリンと、1,1-カルボニルジイミダゾール及びN,O-ジメチルヒドロキシルアミン塩酸塩との反応工程により行う請求項１に記載の2-アセチル-1-ピロリンを製造方法。
2-acetyl according to claim 1, wherein the reaction step is carried out by a reaction step of N-(tert-butoxycarbonyl)-L-proline, 1,1-carbonyldiimidazole and N,O-dimethylhydroxylamine hydrochloride. -Method for producing 1-pyrroline.
- 前記Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリンとN,O-ジメチルヒドロキシルアミンとの反応工程後において、グリニャール反応によってＮ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジンを得る反応工程を含む、請求項１又は２に記載の2-アセチル-1-ピロリンの製造方法。
After the reaction step of the N-(tert-butoxycarbonyl)-L-proline and N,O-dimethylhydroxylamine, a reaction step of obtaining N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine by a Grignard reaction. The method for producing 2-acetyl-1-pyrroline according to claim 1 or 2, comprising:
- 前記グリニャール反応をメチルマグネシウムブロマイドとの反応工程により行う請求項３に記載の2-アセチル-1-ピロリンの製造方法。
4. The method for producing 2-acetyl-1-pyrroline according to claim 3, wherein the Grignard reaction is performed by a reaction step with methylmagnesium bromide.
- 前記Ｎ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジンについて脱保護及び酸化によって、2-アセチル-1-ピロリンを得る反応工程を含む請求項３又は４に記載の2-アセチル-1-ピロリンの製造方法。
2-acetyl-1-pyrroline according to claim 3 or 4, comprising a reaction step of obtaining 2-acetyl-1-pyrroline by deprotecting and oxidizing the N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine. manufacturing method.
- 次の工程（Ａ）～（Ｄ）を含む2-アセチル-1-ピロリンの製造方法。
・工程（Ａ）：Ｎ-(tert-ブトキシカルボニル)-Ｌ-プロリンをアミド化して、Ｎ-メチル-Ｎ-(Ｎ-(tert-ブトキシカルボニル)-L-プロリル)-O-メチルヒドロキルアミンを得る工程
・工程（Ｂ）：Ｎ-メチル-Ｎ-(Ｎ-(tert-ブトキシカルボニル)-L-プロリル)-O-メチルヒドロキルアミンをグリニャール反応によりＮ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジンを得る工程
・工程（Ｃ）：Ｎ-(tert-ブトキシカルボニル)-2-アセチル-ピロリジンの脱保護基を行い2-アセチル-ピロリジンを得る工程。
・工程（Ｄ）:2-アセチル-ピロリジンを酸化して2-アセチル-1-ピロリンを得る工程 A method for producing 2-acetyl-1-pyrroline, comprising the following steps (A) to (D).
・Step (A): N-(tert-butoxycarbonyl)-L-proline is amidated to produce N-methyl-N-(N-(tert-butoxycarbonyl)-L-prolyl)-O-methylhydrokylamine. Obtaining step/step (B): N-methyl-N-(N-(tert-butoxycarbonyl)-L-prolyl)-O-methylhydrokylamine is subjected to Grignard reaction to obtain N-(tert-butoxycarbonyl)-2-acetyl -Process of obtaining pyrrolidine/Step (C): A step of deprotecting N-(tert-butoxycarbonyl)-2-acetyl-pyrrolidine to obtain 2-acetyl-pyrrolidine.
・Step (D): Oxidizing 2-acetyl-pyrrolidine to obtain 2-acetyl-1-pyrroline
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117682974A (en) * | 2024-02-02 | 2024-03-12 | 济南悟通生物科技有限公司 | Preparation method of 2-propionyl-1-pyrroline |
| CN117682974B (en) * | 2024-02-02 | 2024-04-16 | 济南悟通生物科技有限公司 | Preparation method of 2-propionyl-1-pyrroline |
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