JP4899385B2 - Method for producing 3-aminomethyloxetane compound - Google Patents
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本発明は、３−置換−３−アミノメチルオキセタン等の３−アミノメチルオキセタン化合物の新規な製法に関する。３−アミノメチルオキセタン化合物は、医薬、農薬、樹脂等の合成原料や中間体として有用な化合物である。 The present invention relates to a novel process for producing 3-aminomethyloxetane compounds such as 3-substituted-3-aminomethyloxetane. A 3-aminomethyl oxetane compound is a compound useful as a raw material for synthesis or an intermediate for pharmaceuticals, agricultural chemicals, resins and the like.
３−置換−３−アミノメチルオキセタン等の３−アミノメチルオキセタン化合物を製造する方法としては、例えば、３−メチル−３−ｐ−トルエンスルホニルオキシメチルオキセタンとフタルイミドカリウム塩から得られる３−メチル−３−フタルイミドメチルオキセタンを過剰のヒドラジンと反応させた後、過剰のヒドラジンをラネーネッケルで分解することにより、３−メチル−３−アミノメチルオキセタンを収率８１％（フタルイミド体基準）で得る方法が知られている（非特許文献１及び２）。また、３−フェニル−３−フタルイミドメチルオキセタンから同様にして３−フェニル−３−アミノメチルオキセタンを得る方法も知られている（非特許文献３）。 Examples of a method for producing a 3-aminomethyloxetane compound such as 3-substituted-3-aminomethyloxetane include 3-methyl-3-p-toluenesulfonyloxymethyloxetane and 3-methyl-obtained from phthalimide potassium salt. A method for obtaining 3-methyl-3-aminomethyloxetane in a yield of 81% (based on phthalimide form) by reacting 3-phthalimidomethyloxetane with excess hydrazine and then decomposing excess hydrazine with Raney neckel is known. (Non-Patent Documents 1 and 2). In addition, a method for obtaining 3-phenyl-3-aminomethyloxetane in the same manner from 3-phenyl-3-phthalimidomethyloxetane is also known (Non-patent Document 3).
しかしながら、これらの方法は、過剰のヒドラジンを分解するためにその分解工程を必要とするのみならず、フタルイミド化及びヒドラジン分解の工程では特別の反応試剤や触媒を必要とするなど、工業的な製法としてはプロセス的にも経済的にも不利なものであった。更に、後者の方法では収率（フタルイミド体基準）も５４％と低かった。
本発明は、前記問題を解決して、３−置換−３−アミノメチルオキセタン等の３−アミノメチルオキセタン化合物の工業的に好適な製法を提供することを課題とする。即ち、本発明は、一般的な反応試剤を使用して簡便な方法により、３−アミノメチルオキセタン化合物を高収率で得ることができる、プロセス的及び経済的に有利な３−アミノメチルオキセタン化合物の製法を提供することを課題とする。 This invention solves the said problem, and makes it a subject to provide the industrially suitable manufacturing method of 3-aminomethyl oxetane compounds, such as 3-substituted- 3-aminomethyl oxetane. That is, the present invention provides a process- and economically advantageous 3-aminomethyloxetane compound capable of obtaining a 3-aminomethyloxetane compound in a high yield by a simple method using a general reaction reagent. It is an object to provide a manufacturing method.
本発明の課題は、一般式（１）で表される原料オキセタン化合物とアンモニアを反応させて一般式（２）で表される３−アミノメチルオキセタン化合物を生成させることを特徴とする、３−アミノメチルオキセタン化合物の製法により解決される。但し、式中、Ｒは反応に関与しない置換基、Ｘは脱離基を表す。 An object of the present invention is to produce a 3-aminomethyloxetane compound represented by the general formula (2) by reacting a raw material oxetane compound represented by the general formula (1) with ammonia. It is solved by the process for producing aminomethyloxetane compounds. In the formula, R represents a substituent not involved in the reaction, and X represents a leaving group.
前記発明においては、脱離基Ｘは、ハロゲン原子又は有機スルホニルオキシ基であることが好ましく、塩素原子、臭素原子、メタンスルホニルオキシ基、又は、ｐ−トルエンスルホニルオキシ基であることが更に好ましい。また、Ｒはアルキル基であることが好ましい。更に、前記発明においては、アンモニアとしてアンモニア水を使用することが好ましい。 In the invention, the leaving group X is preferably a halogen atom or an organic sulfonyloxy group, more preferably a chlorine atom, a bromine atom, a methanesulfonyloxy group, or a p-toluenesulfonyloxy group. R is preferably an alkyl group. Furthermore, in the said invention, it is preferable to use ammonia water as ammonia.
本発明により、前記問題を解決して、３−置換−３−アミノメチルオキセタン等の３−アミノメチルオキセタン化合物の工業的に好適な製法を提供することができる。即ち、本発明の３−アミノメチルオキセタン化合物の製法は、プロセス的及び経済的に有利なものであり、一般的な反応試剤を使用して簡便な方法により３−置換−３−アミノメチルオキセタン等の３−アミノメチルオキセタン化合物を高収率で得ることができる。 According to the present invention, the above problems can be solved and an industrially suitable process for producing a 3-aminomethyloxetane compound such as 3-substituted-3-aminomethyloxetane can be provided. That is, the method for producing the 3-aminomethyloxetane compound of the present invention is advantageous in terms of process and economy, and a 3-substituted-3-aminomethyloxetane or the like can be produced by a simple method using a general reaction reagent. The 3-aminomethyloxetane compound can be obtained in high yield.
以下、本発明について詳細に説明する。
一般式（１）で表される原料オキセタン化合物において、Ｒは反応に関与しない置換基であり、例えば、アルキル基（好ましくは炭素数１〜１０；メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、ヘプチル基等）、アラルキル基（好ましくは炭素数７〜１０；ベンジル基、フェネチル基、フェニルプロピル基等）、アリール基（好ましくは炭素数６〜１２；フェニル基、トリル基、キシリル基、ナフチル基、アントリル基等）、アルコキシル基（好ましくは炭素数１〜１０；メトキシ基、エトキシ基等）、アミノ基、ニトロ基、カルボキシル基、シアノ基などが挙げられる。その中では、アルキル基、アラルキル基、アリール基が好ましいが、アルキル基が更に好ましく、メチル基、エチル基が特に好ましい。なお、これらの置換基は各種異性体を含み、反応に関与しない限り、他の置換基（アルキル基、アラルキル基、アリール基、アルコキシル基、アミノ基、ニトロ基、カルボキシル基、シアノ基等）を有していてもよく、二重結合等の不飽和結合や、酸素、窒素、硫黄等のヘテロ原子を炭素鎖に含んでいてもよい。
Hereinafter, the present invention will be described in detail.
In the raw material oxetane compound represented by the general formula (1), R is a substituent not involved in the reaction, for example, an alkyl group (preferably having 1 to 10 carbon atoms; a methyl group, an ethyl group, a propyl group, a butyl group, Pentyl group, hexyl group, heptyl group, etc.), aralkyl group (preferably 7-10 carbon atoms; benzyl group, phenethyl group, phenylpropyl group, etc.), aryl group (preferably 6-12 carbon atoms; phenyl group, tolyl group) , Xylyl group, naphthyl group, anthryl group, etc.), alkoxyl group (preferably having 1 to 10 carbon atoms; methoxy group, ethoxy group, etc.), amino group, nitro group, carboxyl group, cyano group and the like. Among them, an alkyl group, an aralkyl group, and an aryl group are preferable, but an alkyl group is more preferable, and a methyl group and an ethyl group are particularly preferable. These substituents include various isomers, and other substituents (alkyl group, aralkyl group, aryl group, alkoxyl group, amino group, nitro group, carboxyl group, cyano group, etc.) can be used unless they are involved in the reaction. The carbon chain may contain an unsaturated bond such as a double bond or a heteroatom such as oxygen, nitrogen, or sulfur.
また、Ｘは脱離基であり、例えば、ハロゲン原子（塩素原子、臭素原子、ヨウ素原子等）、有機スルホニルオキシ基（メタンスルホニルオキシ基、エタンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基、ベンゼンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基等）が挙げられる。その中では、塩素原子、臭素原子、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基が好ましく、特にメタンスルホニルオキシ基が好ましい。 X is a leaving group, for example, halogen atom (chlorine atom, bromine atom, iodine atom, etc.), organic sulfonyloxy group (methanesulfonyloxy group, ethanesulfonyloxy group, trifluoromethanesulfonyloxy group, benzenesulfonyloxy group) Group, p-toluenesulfonyloxy group, etc.). Among them, a chlorine atom, a bromine atom, a methanesulfonyloxy group, and a p-toluenesulfonyloxy group are preferable, and a methanesulfonyloxy group is particularly preferable.
一般式（１）で表される原料オキセタン化合物として、例えば、３−メチル−３−メタンスルホニルオキシメチルオキセタン、３−エチル−３−メタンスルホニルオキシメチルオキセタン、３−メチル−３−ｐ−トルエンスルホニルオキシメチルオキセタン、３−エチル−３−ｐ−トルエンスルホニルオキシメチルオキセタン、３−クロロメチル−３−メチルオキセタン、３−クロロメチル−３−エチルオキセタン、３−ブロモメチル−３−メチルオキセタン、３−ブロモメチル−３−エチルオキセタンなどが具体的に挙げられる。 Examples of the raw material oxetane compound represented by the general formula (1) include 3-methyl-3-methanesulfonyloxymethyloxetane, 3-ethyl-3-methanesulfonyloxymethyloxetane, and 3-methyl-3-p-toluenesulfonyl. Oxymethyloxetane, 3-ethyl-3-p-toluenesulfonyloxymethyloxetane, 3-chloromethyl-3-methyloxetane, 3-chloromethyl-3-ethyloxetane, 3-bromomethyl-3-methyloxetane, 3-bromomethyl Specific examples include -3-ethyloxetane.
一般式（１）で表される原料オキセタン化合物は公知の方法により合成することができる。例えば、３−エチル−３−メタンスルホニルオキシメチルオキセタンは、３−エチル−３−ヒドロキシメチルオキセタンとメタンスルホニルクロライドを反応させて得ることができ（本願参考例１参照）、３−メチル−３−ｐ−トルエンスルホニルオキシメチルオキセタンは、３−メチル−３−ヒドロキシメチルオキセタンとｐ−トルエンスルホニルクロライドを反応させて得ることができる（本願参考例２参照）。また、３−クロロメチル−３−エチルオキセタンなども、３−エチル−３−メタンスルホニルオキシメチルオキセタンとトリエチルアミン塩酸塩から合成できる（本願参考例３参照）。 The raw material oxetane compound represented by the general formula (1) can be synthesized by a known method. For example, 3-ethyl-3-methanesulfonyloxymethyloxetane can be obtained by reacting 3-ethyl-3-hydroxymethyloxetane and methanesulfonyl chloride (see Reference Example 1 of the present application), and 3-methyl-3- p-Toluenesulfonyloxymethyloxetane can be obtained by reacting 3-methyl-3-hydroxymethyloxetane and p-toluenesulfonyl chloride (see Reference Example 2 of the present application). Also, 3-chloromethyl-3-ethyloxetane can be synthesized from 3-ethyl-3-methanesulfonyloxymethyloxetane and triethylamine hydrochloride (see Reference Example 3 of the present application).
アンモニアとしては、アンモニア水、液体アンモニア、アンモニアガスのいずれでも使用することができ、アンモニアを後述の溶媒に溶解したものであってもよい。この中では、一般的であって簡便に使用できることから、アンモニア水が好ましい。このとき、ガス中や溶液中のアンモニアの濃度は特に制限されないが、反応溶媒を使用する場合は溶媒使用量の範囲内で必要量のアンモニアが溶解されていればよく、例えば、アンモニア水であれば、２８質量％アンモニア水が好ましい。アンモニアの使用量は、一般式（１）で表されるオキセタン化合物１モルに対して１〜１００モル、更には１．１〜５０モル、特に１０〜５０モルの範囲であることが好ましい。なお、アンモニアとしてアンモニア水を使用する場合は、その水が後述の反応溶媒となるため、特に反応溶媒を添加する必要はなく、反応溶媒の使用量の範囲で必要量の水を添加する程度でよい。 As ammonia, any of ammonia water, liquid ammonia, and ammonia gas can be used, and ammonia dissolved in a solvent described later may be used. Among these, ammonia water is preferable because it is general and can be used easily. At this time, the concentration of ammonia in the gas or solution is not particularly limited. However, when a reaction solvent is used, it is sufficient that a necessary amount of ammonia is dissolved within the range of the solvent use amount. In this case, 28% by mass aqueous ammonia is preferable. The amount of ammonia used is preferably in the range of 1 to 100 mol, more preferably 1.1 to 50 mol, and particularly preferably 10 to 50 mol with respect to 1 mol of the oxetane compound represented by the general formula (1). In addition, when using ammonia water as ammonia, since the water becomes a reaction solvent described later, it is not necessary to add a reaction solvent in particular, and it is only necessary to add a necessary amount of water within the range of the amount of reaction solvent used. Good.
一般式（１）で表される原料オキセタン化合物とアンモニアとの反応において、反応温度は、０〜２００℃、更には５〜１８０℃、特に５０〜１２０℃であることが好ましく、反応圧力は常圧又は加圧であることが好ましい。 In the reaction of the raw material oxetane compound represented by the general formula (1) with ammonia, the reaction temperature is preferably 0 to 200 ° C., more preferably 5 to 180 ° C., particularly 50 to 120 ° C., and the reaction pressure is usually It is preferably a pressure or a pressure.
反応は、例えば、前記原料オキセタン化合物とアンモニアを混合して攪拌しながら反応させる等の方法によって行われる。このとき、必要に応じて反応溶媒を使用することができ、その使用量は、反応液の均一性や攪拌性により適宜調節されるが、前記原料オキセタン化合物１ｇに対して０〜１００ｇ、更には０〜５０ｇ、特に２〜１５ｇの範囲であることが好ましい。 The reaction is performed by, for example, a method of mixing the raw material oxetane compound and ammonia and reacting them with stirring. At this time, a reaction solvent can be used as necessary, and the amount used is appropriately adjusted depending on the uniformity and stirrability of the reaction solution. It is preferably in the range of 0 to 50 g, particularly 2 to 15 g.
前記反応溶媒は反応を阻害しないものであればよく、水、アルコール類（メタノール、エタノール、イソプロピルアルコール、t-ブチルアルコール、メトキシエタノール、エトキシエタノール、ブトキシエタノール等）、ニトリル類（アセトニトリル、プロピオニトリル、ベンゾニトリル等）、アミド類（Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチルピロリドン等）、尿素類（Ｎ，Ｎ’−ジメチルイミダゾリジノン等）、スルホキシド類（ジメチルスルホキシド等）、スルホン類（スルホラン等）などが挙げられる。この中では、水、アルコール類（中でもメタノール）が好ましいが、水が特に好ましい。 The reaction solvent is not limited as long as it does not inhibit the reaction. Water, alcohols (methanol, ethanol, isopropyl alcohol, t-butyl alcohol, methoxyethanol, ethoxyethanol, butoxyethanol, etc.), nitriles (acetonitrile, propionitrile) , Benzonitrile, etc.), amides (N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc.), ureas (N, N′-dimethylimidazolidinone, etc.), sulfoxides (dimethyl sulfoxide) Etc.) and sulfones (sulfolane etc.). Among these, water and alcohols (particularly methanol) are preferable, but water is particularly preferable.
本発明の反応により、前記原料オキセタン化合物に対応して３−アミノメチル−３−メチル（又はエチル）オキセタン等の３−アミノメチルオキセタン化合物が生成するが、この生成物は、反応終了後、例えば、濾過、中和、抽出、濃縮、蒸留、カラムクロマトグラフィー等の一般的な方法によって単離精製される。 According to the reaction of the present invention, a 3-aminomethyl oxetane compound such as 3-aminomethyl-3-methyl (or ethyl) oxetane is generated corresponding to the raw material oxetane compound. It is isolated and purified by a general method such as filtration, neutralization, extraction, concentration, distillation, column chromatography and the like.
次に、実施例を挙げて本発明を具体的に説明する。 Next, the present invention will be specifically described with reference to examples.
〔参考例１；３−エチル−３−メタンスルホニルオキシメチルオキセタンの合成〕
攪拌装置、温度計及び滴下漏斗を備えた内容積２０００ｍｌのガラス製フラスコに、３−エチル−３−ヒドロキシメチルオキセタン２３２．２ｇ（２．０ｍｏｌ）、トリエチルアミン２４３．０ｇ（２．４ｍｏｌ）及びトルエン１０００ｍｌを加えた後、液温を５〜１０℃に保ちながら、メタンスルホニルクロライド２５２．０ｇ（２．２ｍｏｌ）をゆるやかに加えて、同温度で３時間、室温で３時間攪拌しながら反応させた。
[Reference Example 1; Synthesis of 3-ethyl-3-methanesulfonyloxymethyloxetane]
To a glass flask having an internal volume of 2000 ml equipped with a stirrer, a thermometer and a dropping funnel, 232.2 g (2.0 mol) of 3-ethyl-3-hydroxymethyloxetane, 243.0 g (2.4 mol) of triethylamine and 1000 ml of toluene Then, 252.0 g (2.2 mol) of methanesulfonyl chloride was slowly added while maintaining the liquid temperature at 5 to 10 ° C., and the reaction was allowed to proceed with stirring at the same temperature for 3 hours and at room temperature for 3 hours.
反応終了後、反応液の洗浄（水５００ｍｌ×２回）、その水層の抽出操作（トルエン５００ｍｌ）、全有機層（この有機層＋先の有機層）の洗浄（飽和重曹水５００ｍｌ及び飽和食塩水５００ｍｌ）を行なった。次いで、得られた有機層を無水硫酸マグネシウムで乾燥して濾過した後、濾液を減圧濃縮して溶媒を留去した。得られた残渣を真空乾燥して３−エチル−３−メタンスルホニルオキシメチルオキセタン３０６．６ｇを得た。ガスクロマトグラフィー分析より、このものの純度は８４．０質量％で、単離収率は７８．９％であった。なお、洗浄溶媒及び抽出溶媒は上記括弧内のものを使用した。 After completion of the reaction, the reaction solution was washed (water 500 ml × twice), the aqueous layer was extracted (toluene 500 ml), and the entire organic layer (this organic layer + the previous organic layer) was washed (saturated aqueous sodium bicarbonate 500 ml and saturated sodium chloride). 500 ml of water). Next, the obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure to distill off the solvent. The obtained residue was vacuum-dried to obtain 306.6 g of 3-ethyl-3-methanesulfonyloxymethyloxetane. According to gas chromatography analysis, the purity of the product was 84.0% by mass and the isolated yield was 78.9%. In addition, the thing in the said parenthesis was used for the washing | cleaning solvent and the extraction solvent.
生成物の物性値は以下の通りであった。
（ａ）ＣＩ−ＭＳ（ｍ／ｅ）：１９５（Ｍ＋１）
（ｂ）１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ（ｐｐｍ））：０．９４（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ）、１．８１（３Ｈ，ｑ，Ｊ＝７．３Ｈｚ）、３．０７（３Ｈ，ｓ）、４．４２〜４．４８（４Ｈ，ｍ）
The physical property values of the product were as follows.
(A) CI-MS (m / e): 195 (M + 1)
(B) 1 H-NMR (CDCl 3 , δ (ppm)): 0.94 (3H, t, J = 7.3 Hz), 1.81 (3H, q, J = 7.3 Hz), 3.07 (3H, s), 4.42 to 4.48 (4H, m)
〔参考例２；３−メチル−３−ｐ−トルエンスルホニルオキシメチルオキセタンの合成〕
攪拌装置、温度計、滴下漏斗及び還流冷却器を備えた内容積５００ｍｌのガラス製フラスコに、３−メチル−３−ヒドロキシメチルオキセタン５１．０ｇ（０．５ｍｏｌ）、トルエン３００ｍｌ及びｐ−トルエンスルホニルクロライド１１４．４ｇ（０．６０ｍｏｌ）を加えた後、攪拌しながら０℃まで冷却した。次いで，ピリジン５１．４ｇ（０．６５ｍｏｌ）を同温度で滴下して、同温度で４時間、５０℃で５時間反応させた。
Reference Example 2 Synthesis of 3-methyl-3-p-toluenesulfonyloxymethyl oxetane
In a glass flask having an internal volume of 500 ml equipped with a stirrer, thermometer, dropping funnel and reflux condenser, 51.0 g (0.5 mol) of 3-methyl-3-hydroxymethyloxetane, 300 ml of toluene and p-toluenesulfonyl chloride After adding 114.4 g (0.60 mol), it cooled to 0 degreeC, stirring. Next, 51.4 g (0.65 mol) of pyridine was added dropwise at the same temperature, and the reaction was performed at the same temperature for 4 hours and at 50 ° C. for 5 hours.
反応終了後、反応液の濃縮、濃縮液の抽出処理（酢酸エチル２００ｍｌ＋水２００ｍｌ）、その水層の抽出処理（酢酸エチル２００ｍｌ）、全有機層（この有機層＋先の有機）の洗浄（水１００ｍｌ）を行なった。次いで、得られた有機層を濃縮してヘプタン２００ｍｌを加えた後、析出した白色結晶を濾取して乾燥し、３−メチル−３−ｐ−トルエンスルホニルオキシメチルオキセタン７０．２ｇを得た（収率５４．８％）。 After completion of the reaction, the reaction solution is concentrated, the concentrated solution is extracted (ethyl acetate 200 ml + water 200 ml), the aqueous layer is extracted (ethyl acetate 200 ml), and the entire organic layer (this organic layer + the previous organic) is washed (water 100 ml). Next, the obtained organic layer was concentrated and 200 ml of heptane was added, and then the precipitated white crystals were collected by filtration and dried to obtain 70.2 g of 3-methyl-3-p-toluenesulfonyloxymethyloxetane ( Yield 54.8%).
生成物の物性値は以下の通りであった
（ａ）ＣＩ−ＭＳ（ｍ／ｅ）：２５７（Ｍ＋１）
（ｂ）１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ（ｐｐｍ））：１．３０（３Ｈ，ｓ）、２．４６（３Ｈ，ｓ）、４．１１（２Ｈ，ｓ）、４．３０〜４．３８（４Ｈ，ｍ）、７．３５〜７．３９（２Ｈ，ｍ）、７．７９〜７．８２（２Ｈ，ｍ）
The physical properties of the product were as follows: (a) CI-MS (m / e): 257 (M + 1)
(B) 1 H-NMR (CDCl 3 , δ (ppm)): 1.30 (3H, s), 2.46 (3H, s), 4.11 (2H, s), 4.30-4. 38 (4H, m), 7.35 to 7.39 (2H, m), 7.79 to 7.82 (2H, m)
〔参考例３；３−クロロメチル−３−エチルオキセタンの合成〕
攪拌装置、温度計、滴下漏斗及び還流冷却器を備えた内容積１０００ｍｌのガラス製フラスコに、３−エチル−３−ヒドロキシメチルオキセタン５８．０ｇ（０．５ｍｏｌ）、アセトニトリル３００ｍｌ及びトリエチルアミン６１．０ｇ（０．６１ｍｏｌ）を加えた後、攪拌しながら０℃まで冷却した。次いで、メタンスルホニルクロライド６３ｇ（０．５５ｍｏｌ）を同温度で滴下して３時間反応させた後、室温まで昇温してメタノール２００ｍｌを加え、５０℃で５時間攪拌した。
[Reference Example 3; Synthesis of 3-chloromethyl-3-ethyloxetane]
To a glass flask having an internal volume of 1000 ml equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser, 38.0 g (0.5 mol) of 3-ethyl-3-hydroxymethyloxetane, 300 ml of acetonitrile and 61.0 g of triethylamine ( 0.61 mol) was added and the mixture was cooled to 0 ° C. with stirring. Next, 63 g (0.55 mol) of methanesulfonyl chloride was dropped at the same temperature and reacted for 3 hours, and then the temperature was raised to room temperature, 200 ml of methanol was added, and the mixture was stirred at 50 ° C. for 5 hours.
反応終了後、反応液の濃縮、濃縮液の抽出処理（酢酸エチル２００ｍｌ＋水１００ｍｌ）、その水層の抽出処理（酢酸エチル１００ｍｌ）、全有機層（この有機層＋先の有機層）の洗浄（水１００ｍｌ）を行なった。次いで、得られた有機層を濃縮し、この濃縮液１０５．７ｇに塩化リチウム２３．２ｇ（０．５４５ｍｏｌ））とメタノール２００ｍｌを加えて室温で５時間攪拌した後、６０℃で６時間反応させた。 After completion of the reaction, the reaction solution is concentrated, the concentrated solution is extracted (ethyl acetate 200 ml + water 100 ml), the aqueous layer is extracted (ethyl acetate 100 ml), and the entire organic layer (this organic layer + the previous organic layer) is washed ( 100 ml of water). Next, the obtained organic layer was concentrated, and 23.2 g (0.545 mol) of lithium chloride and 200 ml of methanol were added to 105.7 g of this concentrated liquid and stirred for 5 hours at room temperature, followed by reaction at 60 ° C. for 6 hours. It was.
反応終了後、反応液の冷却及び濾過、濾液の濃縮、濃縮液の抽出処理（酢酸エチル２００ｍｌ＋水１００ｍｌ）、その水層の抽出処理（酢酸エチル１００ｍ）、全有機層（この有機層＋先の有機層）の洗浄（水１００ｍｌ）を行なった。次いで、得られた有機層を濃縮した後、蒸留（３．５ｋＰａ、７９〜８０℃）により、３−クロロメチル−３−エチルオキセタン４４．２ｇを得た（収率６５．４％）。ガスクロマトグラフィー分析より、このものの純度は面積百分率で９９．６％であった。 After completion of the reaction, the reaction solution is cooled and filtered, the filtrate is concentrated, the concentrate is extracted (ethyl acetate 200 ml + water 100 ml), the aqueous layer is extracted (ethyl acetate 100 m), the entire organic layer (this organic layer + the previous layer) The organic layer) was washed (100 ml of water). Next, after the obtained organic layer was concentrated, 44.2 g of 3-chloromethyl-3-ethyloxetane was obtained by distillation (3.5 kPa, 79 to 80 ° C.) (yield 65.4%). According to gas chromatographic analysis, the purity of this product was 99.6% in area percentage.
生成物の物性値は以下の通りであった。
（ａ）ＣＩ−ＭＳ（ｍ／ｅ）：１３５（Ｍ＋１）
（ｂ）１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ（ｐｐｍ））：０．９０（３Ｈ，ｔ，Ｊ＝７．４Ｈｚ）、１．８５（２Ｈ，ｑ，Ｊ＝７．４Ｈｚ）、３．７９（２Ｈ，ｓ）、４．４２（４Ｈ，ｓ）
The physical property values of the product were as follows.
(A) CI-MS (m / e): 135 (M + 1)
(B) 1 H-NMR (CDCl 3 , δ (ppm)): 0.90 (3H, t, J = 7.4 Hz), 1.85 (2H, q, J = 7.4 Hz), 3.79 (2H, s), 4.42 (4H, s)
〔参考例４；３−ブロモメチル−３−エチルオキセタンの合成〕
塩化リチウムを臭化リチウム一水和物５７．１（０．５４５ｍｏｌ）に代え、反応終了後の蒸留条件を２．０ｋＰａ／７５〜８０℃に変えた以外は、参考例３と同様に反応と生成物の単離生成を行なって、３−ブロモメチル−３−エチルオキセタン６５．１ｇを得た（収率７２．０％）。ガスクロマトグラフィー分析より、このものの純度は面積百分率で９９．０％であった。
Reference Example 4 Synthesis of 3-bromomethyl-3-ethyloxetane
The reaction was performed in the same manner as in Reference Example 3 except that lithium chloride was replaced with lithium bromide monohydrate 57.1 (0.545 mol) and the distillation conditions after the reaction were changed to 2.0 kPa / 75 to 80 ° C. The product was isolated and produced to obtain 65.1 g of 3-bromomethyl-3-ethyloxetane (yield 72.0%). According to gas chromatographic analysis, the purity of this product was 99.0% as an area percentage.
生成物の物性値は以下の通りであった。
（ａ）ＣＩ−ＭＳ（ｍ／ｅ）：１８０（Ｍ＋１）、１８３（Ｍ＋１）
（ｂ）１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ（ｐｐｍ））：０．８８（３Ｈ，ｔ，Ｊ＝７．６Ｈｚ）、１．８７（２Ｈ，ｑ，Ｊ＝７．６Ｈｚ）、３．６９（２Ｈ，ｓ）、４．４０（４Ｈ，ｍ）
The physical property values of the product were as follows.
(A) CI-MS (m / e): 180 (M + 1), 183 (M + 1)
(B) 1 H-NMR (CDCl 3 , δ (ppm)): 0.88 (3H, t, J = 7.6 Hz), 1.87 (2H, q, J = 7.6 Hz), 3.69 (2H, s), 4.40 (4H, m)
〔実施例１；３−アミノメチル−３−エチルオキセタンの製造〕
攪拌装置、温度計及び圧力ゲージを備えた内容積１０００ｍｌの耐圧反応器に、参考例１で得られた３−エチル−３−メタンスルホニルオキシメチルオキセタン８９．０ｇ（３８５ｍｍｏｌ）と２８質量％アンモニア水７０３ｇ（１１．５５ｍｏｌ）を加え、攪拌しながら８０〜９０℃で６時間反応させた。
[Example 1; Production of 3-aminomethyl-3-ethyloxetane]
In a pressure-resistant reactor having an internal volume of 1000 ml equipped with a stirrer, a thermometer, and a pressure gauge, 89.0 g (385 mmol) of 3-ethyl-3-methanesulfonyloxymethyloxetane obtained in Reference Example 1 and 28% by mass aqueous ammonia 703g (11.55mol) was added and it was made to react at 80-90 degreeC for 6 hours, stirring.
反応終了後、反応液を室温まで冷却し、５０質量％の水酸化ナトリウム水溶液３０．８ｇ（３８５ｍｍｏｌ）と塩化ナトリウム１３５ｇを加えて３０分間攪拌した。反応液をガスクロマトグラフィーにより分析したところ、３−アミノメチル−３−エチルオキセタン４１．１ｇが生成していた（収率９３％）。次いで、反応液の抽出処理（２−ブタノール３００ｍｌ×３回）及び有機層の減圧濃縮を行なって得られた残渣にテトラエチレンペンタミン１５ｇを加えた後、蒸留（２００〜４００ｋＰａ、７５〜８５℃）により、３−アミノメチル−３−エチルオキセタン３４．８ｇを得た（単離収率７８％）。ガスクロマトグラフィー分析より、このものの純度は面積百分率で９９％であった。 After completion of the reaction, the reaction solution was cooled to room temperature, 30.8 g (385 mmol) of a 50 mass% sodium hydroxide aqueous solution and 135 g of sodium chloride were added, and the mixture was stirred for 30 minutes. When the reaction solution was analyzed by gas chromatography, 41.1 g of 3-aminomethyl-3-ethyloxetane was produced (yield 93%). Next, 15 g of tetraethylenepentamine was added to the residue obtained by extracting the reaction solution (2-butanol 300 ml × 3 times) and concentrating the organic layer under reduced pressure, followed by distillation (200 to 400 kPa, 75 to 85 ° C. ) Gave 34.8 g of 3-aminomethyl-3-ethyloxetane (isolation yield 78%). According to gas chromatographic analysis, the purity of this product was 99% in area percentage.
生成物の物性値は以下の通りであった。
（ａ）ＣＩ−ＭＳ（ｍ／ｅ）：１１６（Ｍ＋１）
（ｂ）１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ（ｐｐｍ））：０．８９（３Ｈ，ｔ，Ｊ＝７．６Ｈｚ）、１．３０（１Ｈ，ｂｒｓ）、１．７１（２Ｈ，ｑ，Ｊ＝７．６Ｈｚ）、２．９３（２Ｈ，ｓ）、４．３９（４Ｈ，ｓ）
The physical property values of the product were as follows.
(A) CI-MS (m / e): 116 (M + 1)
(B) 1 H-NMR (CDCl 3 , δ (ppm)): 0.89 (3H, t, J = 7.6 Hz), 1.30 (1H, brs), 1.71 (2H, q, J = 7.6 Hz), 2.93 (2H, s), 4.39 (4H, s)
〔実施例２；３−アミノメチル−３−エチルオキセタンの製造〕
攪拌装置、温度計及び圧力ゲージを備えた内容積５０ｍｌの耐圧反応器に、３−エチル−３−メタンスルホニルオキシメチルオキセタン１．０ｇ（５．１５ｍｍｏｌ）と２８質量％アンモニア水９．４ｇ（１５５ｍｍｏｌ）を加え、攪拌しながら６０〜７０℃で６時間反応させた。反応終了後、室温まで冷却して反応液をガスクロマトグラフィーで分析したところ、３−アミノメチル−３−エチルオキセタン５４０ｍｇが生成していた（収率９２％）。
[Example 2; Production of 3-aminomethyl-3-ethyloxetane]
To a pressure-resistant reactor having an internal volume of 50 ml equipped with a stirrer, a thermometer and a pressure gauge, 1.0 g (5.15 mmol) of 3-ethyl-3-methanesulfonyloxymethyloxetane and 9.4 g (155 mmol) of 28% by mass aqueous ammonia were added. ) And reacted at 60 to 70 ° C. for 6 hours with stirring. After completion of the reaction, the reaction solution was cooled to room temperature and analyzed by gas chromatography. As a result, 540 mg of 3-aminomethyl-3-ethyloxetane was produced (yield 92%).
〔実施例３；３−アミノメチル−３−メチルオキセタンの製造〕
実施例２と同様の反応器に、参考例２で得られた３−メチル−３−ｐ−トルエンスルホニルオキシメチルオキセタン５．１２ｇ（２０．０ｍｍｏｌ）と２８質量％アンモニア水３６．５ｇ（６００ｍｍｏｌ）を加え、攪拌しながら１００〜１１０℃で１２時間反応させた。反応終了後、室温まで冷却して反応液をガスクロマトグラフィーで分析したところ、３−アミノメチル−３−メチルオキセタン１．７２ｇが生成していた（収率８５％）。
Example 3 Production of 3-aminomethyl-3-methyloxetane
In the same reactor as in Example 2, 5.12 g (20.0 mmol) of 3-methyl-3-p-toluenesulfonyloxymethyl oxetane obtained in Reference Example 2 and 36.5 g (600 mmol) of 28% by mass aqueous ammonia. Was added and reacted at 100-110 ° C. for 12 hours with stirring. After completion of the reaction, the reaction solution was cooled to room temperature and analyzed by gas chromatography. As a result, 1.72 g of 3-aminomethyl-3-methyloxetane was produced (yield 85%).
生成物の物性値は以下の通りであった。
（ａ）ＣＩ−ＭＳ（ｍ／ｅ）：１０２（Ｍ＋１）
（ｂ）１Ｈ−ＮＭＲ（ＣＤＣｌ３，δ（ｐｐｍ））：１．２８（３Ｈ，ｓ）、１．３０〜１．６０（１Ｈ，ｂｒｓ）、２．８９（２Ｈ，ｓ）、４．３８（２Ｈ，ｄ，Ｊ＝５．９Ｈｚ）、４．４４（２Ｈ，ｄ，Ｊ＝５．９Ｈｚ）
The physical property values of the product were as follows.
(A) CI-MS (m / e): 102 (M + 1)
(B) 1 H-NMR (CDCl 3 , δ (ppm)): 1.28 (3H, s), 1.30 to 1.60 (1H, brs), 2.89 (2H, s), 4. 38 (2H, d, J = 5.9 Hz), 4.44 (2H, d, J = 5.9 Hz)
〔実施例４；３−アミノメチル−３−エチルオキセタンの製造〕
実施例２と同様の反応器に、参考例３で得られた３−クロロメチル−３−エチルオキセタン１．３５ｇ（１０．０ｍｍｏｌ）と２８質量％アンモニア水１８．２ｇ（３００ｍｍｏｌ）を加え、攪拌しながら１００〜１１０℃で６時間反応させた。反応終了後、室温まで冷却して反応液をガスクロマトグラフィーで分析したところ、３−アミノメチル−３−エチルオキセタン１．０ｇが生成していた（収率８７％）。
Example 4 Production of 3-aminomethyl-3-ethyloxetane
To the same reactor as in Example 2, 1.35 g (10.0 mmol) of 3-chloromethyl-3-ethyloxetane obtained in Reference Example 3 and 18.2 g (300 mmol) of 28% by mass aqueous ammonia were added and stirred. The reaction was carried out at 100 to 110 ° C. for 6 hours. After completion of the reaction, the reaction solution was cooled to room temperature and analyzed by gas chromatography. As a result, 1.0 g of 3-aminomethyl-3-ethyloxetane was produced (yield 87%).
〔実施例５；３−アミノメチル−３−エチルオキセタンの製造〕
実施例２と同様の反応器に、参考例４で得られた３−ブロモメチル−３−エチルオキセタン１．８１ｇ（１０．０ｍｍｏｌ）と２８質量％アンモニア水１８．２ｇ（３００ｍｍｏｌ）を加え、攪拌しながら１００〜１１０℃で６時間反応させた。反応終了後、室温まで冷却して反応液をガスクロマトグラフィーで分析したところ、３−アミノメチル−３−エチルオキセタン１．０３ｇが生成していた（収率８９％）。
Example 5 Production of 3-aminomethyl-3-ethyloxetane
To the same reactor as in Example 2, 1.81 g (10.0 mmol) of 3-bromomethyl-3-ethyloxetane obtained in Reference Example 4 and 18.2 g (300 mmol) of 28 mass% aqueous ammonia were added and stirred. The reaction was carried out at 100 to 110 ° C. for 6 hours. After completion of the reaction, the reaction solution was cooled to room temperature and analyzed by gas chromatography. As a result, 1.03 g of 3-aminomethyl-3-ethyloxetane was produced (yield 89%).
本発明により、３−アミノメチル−３−メチル（又はエチル）オキセタン等の３−アミノメチルオキセタン化合物を工業的に好適な製法によって高収率で製造できる。このような３−アミノメチルオキセタン化合物は、医薬、農薬、樹脂等の合成原料や中間体として有用な化合物である。 According to the present invention, a 3-aminomethyloxetane compound such as 3-aminomethyl-3-methyl (or ethyl) oxetane can be produced in a high yield by an industrially suitable production method. Such a 3-aminomethyl oxetane compound is a useful compound as a raw material for synthesis or an intermediate for pharmaceuticals, agricultural chemicals, resins and the like.
Claims (5)
A process for producing a 3-aminomethyloxetane compound represented by the general formula (2) by reacting a raw material oxetane compound represented by the general formula (1) with ammonia, and using ammonia water as ammonia. A method for producing a 3-aminomethyloxetane compound, which is characterized. (In the formula, R represents a substituent not involved in the reaction, and X represents a leaving group.)
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| AR099134A1 (en) * | 2014-01-24 | 2016-06-29 | Hoffmann La Roche | PROCEDURE FOR THE PREPARATION OF N - [(3-AMINOOXETAN-3-IL) METHYL] -2- (1,1-DIOXO-3,5-DIHIDRO-1,4-BENZOTIAZEPÍN-4-IL) -6-METIL- QUINAZOLÍN-4-AMINA |
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