JP2013151452A - Imine derivative containing optically activity trifluoromethyl group, method of manufacturing the same, and method of manufacturing optical activity amine derivative containing trifluoromethyl group using the same - Google Patents
Imine derivative containing optically activity trifluoromethyl group, method of manufacturing the same, and method of manufacturing optical activity amine derivative containing trifluoromethyl group using the same Download PDFInfo
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Abstract
Description
本発明は、新規な光学活性トルフルオロメチル基含有イミン誘導体、その製造方法並びにそれを用いたトリフルオロメチル基含有光学活性アミン誘導体の製造方法に関する。光学活性トルフルオロメチル基含有イミン誘導体は医農薬の合成中間体や電子材料の合成中間体として有用な化合物である。 The present invention relates to a novel optically active trifluoromethyl group-containing imine derivative, a process for producing the same, and a process for producing a trifluoromethyl group-containing optically active amine derivative using the same. An optically active trifluoromethyl group-containing imine derivative is a useful compound as a synthetic intermediate for medical and agricultural chemicals and a synthetic intermediate for electronic materials.
本発明の光学活性トルフルオロメチル基含有イミン誘導体は知られていない。 The optically active trifluoromethyl group-containing imine derivative of the present invention is not known.
従来技術として、光学活性１−フェニルエチル−１−アミンとトリフルオロアセトアルデヒドから調製されるトリフルオロメチル １−フェニルエチル−１−イミンやジフルオロメチル １−フェニルエチル−１−イミン等が知られており、各種光学活性化合物の製造等に用いられている（非特許文献１，２）。 As conventional techniques, trifluoromethyl 1-phenylethyl-1-imine and difluoromethyl 1-phenylethyl-1-imine prepared from optically active 1-phenylethyl-1-amine and trifluoroacetaldehyde are known. And used for the production of various optically active compounds (Non-Patent Documents 1 and 2).
また、光学活性１−フェニル−２−メトキシエチル−１−アミンとトリフルオロアセトアルデヒドから調製されるトリフルオロメチル １−フェニル−２−メトキシエチル−１−イミンも知られており、各種光学活性化合物の製造等に用いられている（非特許文献３）。 Further, trifluoromethyl 1-phenyl-2-methoxyethyl-1-imine prepared from optically active 1-phenyl-2-methoxyethyl-1-amine and trifluoroacetaldehyde is also known. It is used for manufacturing and the like (Non-Patent Document 3).
従来の非特許文献１または非特許文献２に記載の光学活性トリフルオロメチル １−フェニルエチル−１−イミンやジフルオロメチル １−フェニルエチル−１−イミンは各種反応に用いた場合、ある程度の立体選択性は発現するが満足できるものではない。 When optically active trifluoromethyl 1-phenylethyl-1-imine or difluoromethyl 1-phenylethyl-1-imine described in the conventional Non-Patent Document 1 or Non-Patent Document 2 is used in various reactions, a certain degree of stereoselection is obtained. Sex is manifested but not satisfactory.
一方、非特許文献３に記載の光学活性トリフルオロメチル １−フェニル−２−メトキシエチル−１−イミンは各種反応において比較的高い立体選択性を発現するが、原料として用いる光学活性１−フェニル−２−メトキシエチル−１−アミンの合成に高価なヨードメタンを用い、また低収率のため、工業的に使用可能な原料とはいえない。 On the other hand, optically active trifluoromethyl 1-phenyl-2-methoxyethyl-1-imine described in Non-Patent Document 3 exhibits relatively high stereoselectivity in various reactions, but optically active 1-phenyl- used as a raw material. Since iodomethane, which is expensive for the synthesis of 2-methoxyethyl-1-amine, is used and the yield is low, it cannot be said to be an industrially usable raw material.
本発明者らは、高い立体選択性を発現し、かつ工業的に利用可能な光学活性トリフルオロメチル基含有イミン誘導体について、鋭意検討を行った結果、安価かつ工業的に高い収率で原料が調製でき、高い立体選択性を発現する光学活性トリフルオロメチル基含有１−フェニル−２−エトキシエチル−１−イミン誘導体を見出し、本発明を完成させるに至った。 As a result of intensive investigations on an optically active trifluoromethyl group-containing imine derivative that expresses high stereoselectivity and is industrially usable, the raw materials can be obtained at a low cost and in an industrially high yield. An optically active trifluoromethyl group-containing 1-phenyl-2-ethoxyethyl-1-imine derivative that can be prepared and exhibits high stereoselectivity has been found, and the present invention has been completed.
すなわち、本発明は、
［項１］ 下記一般式（１）
That is, the present invention
[Claim 1] The following general formula (1)
（式中、ｎは０〜２の整数を示す）
または、下記一般式（２）
(In the formula, n represents an integer of 0 to 2)
Or the following general formula (2)
で表されるトリフルオロメチル基含有イミン誘導体。
A trifluoromethyl group-containing imine derivative represented by:
［項２］ 下記式（３） [Claim 2] The following formula (3)
ＣＦ３（ＣＨ２）ｎＣＨＯ （５）
（式中、ｎは０〜２の整数を示す）
で表されるトリフルオロメチル基含有アルデヒドまたは、下記一般式（６）
ＣＦ３（ＣＨ２）ｎＣＨ（ＯＨ）２ （６）
（式中ｎは前記に同じ）
で表されるトリフルオロメチル基含有アルデヒド−水和物を、酸触媒存在下、脱水反応を行うことを特徴とする下記一般式（１）
CF 3 (CH 2 ) n CHO (5)
(In the formula, n represents an integer of 0 to 2)
A trifluoromethyl group-containing aldehyde represented by the following general formula (6)
CF 3 (CH 2) n CH (OH) 2 (6)
(Where n is the same as above)
A trifluoromethyl group-containing aldehyde-hydrate represented by the following general formula (1), which is subjected to a dehydration reaction in the presence of an acid catalyst:
または下記一般式（２）
Or the following general formula (2)
で表されるトリフルオロメチル基含有イミン誘導体の製造方法。
The manufacturing method of the trifluoromethyl group containing imine derivative represented by these.
［項３］ 下記一般式（１） [Claim 3] The following general formula (1)
または下記一般式（２）
Or the following general formula (2)
で表されるトリフルオロメチル基含有イミン誘導体と下記一般式（７）
A trifluoromethyl group-containing imine derivative represented by the following general formula (7)
で表されるアリルハライド類を亜鉛の存在下に反応させることを特徴とする下記一般式
または下記一般式（９）
で表される含フッ素アミン誘導体の製造方法
を提供するものである。
Wherein allyl halides represented by the formula are reacted in the presence of zinc
Or the following general formula (9)
The manufacturing method of the fluorine-containing amine derivative represented by these is provided.
本発明により、医農薬や電子材料の合成中間体として有用な、光学活性トリフルオロメチル基含有イミン誘導体が提案された。 According to the present invention, an optically active trifluoromethyl group-containing imine derivative useful as a synthetic intermediate for medical and agricultural chemicals and electronic materials has been proposed.
以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
本発明の一般式（１）または一般式（２）で表される光学活性トリフルオロメチル基含有イミン誘導体は、具体的には例えば、（Ｒ）−トリフルオロメチル ２−エトキシ−１−フェニルエチル−１−イミン、（Ｒ）−２，２，２−トリフルオロエチル ２−エトキシ−１−フェニルエチル−１−イミン、（Ｒ）−３，３，３−トリフルオロ−ｎ−プロピル ２−エトキシ−１−フェニルエチル−１−イミン、（Ｒ）−４，４，４−トリフルオロ−ｎ−ブチル ２−エトキシ−１−フェニルエチル−１−イミン、（Ｓ）−トリフルオロメチル ２−エトキシ−１−フェニルエチル−１−イミン、（Ｓ）−２，２，２−トリフルオロエチル ２−エトキシ−１−フェニルエチル−１−イミン、（Ｓ）−３，３，３−トリフルオロ−ｎ−プロピル ２−エトキシ−１−フェニルエチル−１−イミン、（Ｓ）−４，４，４−トリフルオロ−ｎ−ブチル ２−エトキシ−１−フェニルエチル−１−イミン等が挙げられる。 Specific examples of the optically active trifluoromethyl group-containing imine derivative represented by the general formula (1) or the general formula (2) of the present invention include (R) -trifluoromethyl 2-ethoxy-1-phenylethyl. -1-imine, (R) -2,2,2-trifluoroethyl 2-ethoxy-1-phenylethyl-1-imine, (R) -3,3,3-trifluoro-n-propyl 2-ethoxy -1-phenylethyl-1-imine, (R) -4,4,4-trifluoro-n-butyl 2-ethoxy-1-phenylethyl-1-imine, (S) -trifluoromethyl 2-ethoxy- 1-phenylethyl-1-imine, (S) -2,2,2-trifluoroethyl 2-ethoxy-1-phenylethyl-1-imine, (S) -3,3,3-trifluoro-n- Propyl 2 Ethoxy-1-phenylethyl-1-imine include (S)-4,4,4-trifluoro -n- butyl 2-ethoxy-1-phenylethyl-1-imine.
本発明の光学活性トリフルオロメチル基含有イミン誘導体の調製に使用する光学活性１−フェニル−２−エトキシエチル−１−アミンは、市販の光学活性フェニルグリシノールとヨードエタンを塩基存在下、反応させることにより高収率で調製される。 The optically active 1-phenyl-2-ethoxyethyl-1-amine used for the preparation of the optically active trifluoromethyl group-containing imine derivative of the present invention is obtained by reacting commercially available optically active phenylglycinol with iodoethane in the presence of a base. In a high yield.
本発明の光学活性トリフルオロメチル基含有イミン誘導体は、前記光学活性１−フェニル−２−エトキシエチル−１−アミンとトリフルオロメチル基含有アルデヒドまたはその水和物を酸触媒存在下、脱水反応を行うことにより調製される。 The optically active trifluoromethyl group-containing imine derivative of the present invention comprises a dehydration reaction of the optically active 1-phenyl-2-ethoxyethyl-1-amine and a trifluoromethyl group-containing aldehyde or hydrate thereof in the presence of an acid catalyst. It is prepared by doing.
本発明に適用可能なトリフルオロメチル基含有アルデヒドとしては、具体的には例えば、トリフルオロアセトアルデヒド、３，３，３−トリフルオロプロピルアルデヒド、４，４，４−トリフルオロブチルアルデヒド、５，５，５−トリフルオロペンチルアルデヒド等が挙げられる。
本発明に適用可能なトリフルオロメチル基含有アルデヒド・水和物としては、トリフルオロアセトアルデヒド・水和物、３，３，３−トリフルオロプロピルアルデヒド・水和物、４，４，４−トリフルオロブチルアルデヒド・水和物、５，５，５−トリフルオロペンチルアルデヒド・水和物等が挙げられる。
Specific examples of the trifluoromethyl group-containing aldehyde applicable to the present invention include trifluoroacetaldehyde, 3,3,3-trifluoropropylaldehyde, 4,4,4-trifluorobutyraldehyde, 5,5. , 5-trifluoropentylaldehyde and the like.
Examples of the trifluoromethyl group-containing aldehyde / hydrate applicable to the present invention include trifluoroacetaldehyde / hydrate, 3,3,3-trifluoropropylaldehyde / hydrate, 4,4,4-trifluoro. Examples include butyraldehyde / hydrate, 5,5,5-trifluoropentylaldehyde / hydrate, and the like.
本発明に適用可能なトリフルオロメチル基含有アルデヒドまたはその水和物の使用量としては、反応に具する光学活性１−フェニル−２−エトキシエチル−１−アミンに対して、１．０モル以上の使用で可能であるが、収率及び経済性の面で好ましくは１．２〜４．０モル量使用する。 The amount of the trifluoromethyl group-containing aldehyde or hydrate thereof applicable to the present invention is 1.0 mol or more based on the optically active 1-phenyl-2-ethoxyethyl-1-amine included in the reaction. In terms of yield and economy, it is preferably used in an amount of 1.2 to 4.0 moles.
本発明のトリフルオロメチル基含有アルデヒドまたはその水和物と光学活性１−フェニル−２−エトキシエチル−１−アミンの反応に適用可能な酸触媒としては、具体的には例えば硫酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ−トルエンスルホン酸、ｐ−トルエンスルホン酸・ピリジニウム塩等が挙げられ、反応に具する光学活性１−フェニル−２−エトキシエチル−１−アミンに対して、０．００１〜０．１モル量使用する。 Specific examples of the acid catalyst applicable to the reaction of the trifluoromethyl group-containing aldehyde of the present invention or a hydrate thereof with optically active 1-phenyl-2-ethoxyethyl-1-amine include sulfuric acid and methanesulfonic acid. Benzenesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid / pyridinium salt, etc., and 0.001 to the optically active 1-phenyl-2-ethoxyethyl-1-amine included in the reaction 0.1 molar amount is used.
本発明のトリフルオロメチル基含有アルデヒドまたはその水和物と光学活性１−フェニル−２−エトキシエチル−１−アミンの反応に適用可能な溶剤としては、反応に不活性かつ水と均一に混じらない溶剤であればあらゆるものが使用可能であるが、水と共沸するものが好ましく、具体的には例えば、ベンゼン、トルエン、エチルベンゼン、キシレン、クメン等の芳香族炭化水素系溶剤が挙げられ、その使用量は、反応に具する光学活性１−フェニル−２−エトキシエチル−１−アミンに対して５〜１００重量倍量使用する。 The solvent applicable to the reaction of the trifluoromethyl group-containing aldehyde of the present invention or a hydrate thereof with optically active 1-phenyl-2-ethoxyethyl-1-amine is inert to the reaction and does not mix uniformly with water. Any solvent can be used, but those azeotropic with water are preferred, and specific examples include aromatic hydrocarbon solvents such as benzene, toluene, ethylbenzene, xylene, cumene, and the like. The amount used is 5 to 100 times by weight with respect to the optically active 1-phenyl-2-ethoxyethyl-1-amine included in the reaction.
本発明のトリフルオロメチル基含有アルデヒドまたはその水和物と光学活性１−フェニル−２−エトキシエチル−１−アミンの反応温度としては、使用する溶剤の沸点で、還流下反応を行う。共沸により留去された水は、水分離器（ディーン・スターク）で分離、除去する。 As the reaction temperature of the trifluoromethyl group-containing aldehyde of the present invention or a hydrate thereof and optically active 1-phenyl-2-ethoxyethyl-1-amine, the reaction is carried out under reflux at the boiling point of the solvent used. The water distilled off azeotropically is separated and removed by a water separator (Dean Stark).
本発明で得られた光学活性トリフルオロメチル基含有イミン誘導体は、通常、反応液を濃縮ｓの後、減圧下での蒸留等により精製する。
本発明で得られた一般式（１）または一般式（２）で表される光学活性トリフルオロメチル基含有イミン誘導体と一般式（７）で表されるアリルハライド類とを亜鉛の存在下に反応させることにより得られる一般式（８）または一般式（９）で表される含フッ素アミン誘導体としては、具体的には例えば、（１'Ｓ，４Ｒ）−４−（２'−エトキシ−１'−フェニルエチル−１'−アミノ）−５，５，５−トリフルオロ−１−ペンテン、（１'Ｓ，４Ｒ）−４−（２'−エトキシ−１'−フェニルエチル−１'−アミノ）−６，６，６−トリフルオロ−１−ヘキセン、（１'Ｓ，４Ｓ）−４−（２'−エトキシ−１'−フェニルエチル−１'−アミノ）−７，７，７−トリフルオロ−１−ヘプテン、（１'Ｒ，４Ｓ）−４−（２'−エトキシ−１'−フェニルエチル−１'−アミノ）−５，５，５−トリフルオロ−１−ペンテン、（１'Ｒ，４Ｓ）−４−（２'−エトキシ−１'−フェニルエチル−１'−アミノ）−６，６，６−トリフルオロ−１−ヘキセン、（１'Ｒ，４Ｒ）−４−（２'−エトキシ−１'−フェニルエチル−１'−アミノ）−７，７，７−トリフルオロ−１−ヘプテン等が挙げられる。
The optically active trifluoromethyl group-containing imine derivative obtained in the present invention is usually purified by concentrating the reaction solution and distilling under reduced pressure or the like.
The optically active trifluoromethyl group-containing imine derivative represented by the general formula (1) or the general formula (2) obtained in the present invention and the allyl halides represented by the general formula (7) in the presence of zinc. Specific examples of the fluorine-containing amine derivative represented by the general formula (8) or the general formula (9) obtained by the reaction include (1 ′S, 4R) -4- (2′-ethoxy-). 1'-phenylethyl-1'-amino) -5,5,5-trifluoro-1-pentene, (1'S, 4R) -4- (2'-ethoxy-1'-phenylethyl-1'- Amino) -6,6,6-trifluoro-1-hexene, (1 ′S, 4S) -4- (2′-ethoxy-1′-phenylethyl-1′-amino) -7,7,7- Trifluoro-1-heptene, (1′R, 4S) -4- (2′-ethoxy-1′-phenylethyl) -1′-amino) -5,5,5-trifluoro-1-pentene, (1′R, 4S) -4- (2′-ethoxy-1′-phenylethyl-1′-amino) -6, 6,6-trifluoro-1-hexene, (1′R, 4R) -4- (2′-ethoxy-1′-phenylethyl-1′-amino) -7,7,7-trifluoro-1- Examples include heptene.
本発明の一般式（７）で表されるアリルハライド類としては、具体的には例えば、アリルクロリド、アリルブロミド、アリルヨージド等が挙げられる。 Specific examples of the allyl halides represented by the general formula (7) of the present invention include allyl chloride, allyl bromide, allyl iodide and the like.
本発明の一般式（７）で表されるアリルハライド類の使用量としては、反応に具する一般式（１）または一般式（２）で表される光学活性トリフルオロメチル基含有イミン誘導体に対して、等モルで実施可能であるが、通常反応を完結するために、１．２〜３．０モル量使用する。 The use amount of allyl halides represented by the general formula (7) of the present invention includes the optically active trifluoromethyl group-containing imine derivative represented by the general formula (1) or the general formula (2) included in the reaction. On the other hand, it can be carried out in an equimolar amount, but is usually used in an amount of 1.2 to 3.0 mol in order to complete the reaction.
本発明で得られた一般式（１）または一般式（２）で表される光学活性トリフルオロメチル基含有イミン誘導体と一般式（７）で表されるアリルハライド類との反応に適用可能な溶剤としては、反応に不活性なものであれば特に規定はないが、具体的には例えば、ジクロロメタン、クロロホルム等のハロゲン化炭化水素系溶剤、ベンゼン、トルエン、エチルベンゼン等の芳香族炭化水素系溶剤、ジメチルエーテル、ジイソプロピルエーテル、メチル−ｔｅｒｔ−ブチルエーテル、テトラヒドロフラン等のエ−テル系溶剤が挙げられ、通常、反応に具する本発明の一般式（７）で表されるブタジエン誘導体に使用量としては、反応に具する一般式（１）または一般式（２）で表される光学活性トリフルオロメチル基含有イミン誘導体に対して、５〜５０重量倍量使用する。 Applicable to the reaction of the optically active trifluoromethyl group-containing imine derivative represented by the general formula (1) or the general formula (2) obtained in the present invention and the allyl halides represented by the general formula (7). The solvent is not particularly limited as long as it is inert to the reaction. Specifically, for example, halogenated hydrocarbon solvents such as dichloromethane and chloroform, and aromatic hydrocarbon solvents such as benzene, toluene and ethylbenzene. , Ether solvents such as dimethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran and the like. Usually, the amount used for the butadiene derivative represented by the general formula (7) of the present invention to be reacted is as follows: For the optically active trifluoromethyl group-containing imine derivative represented by the general formula (1) or the general formula (2) included in the reaction, 50 times by weight to use.
本発明で得られた一般式（１）または一般式（２）で表される光学活性トリフルオロメチル基含有イミン誘導体と一般式（７）で表されるアリルハライド類との反応に用いる亜鉛は工業的または試薬として入手可能な粉末であれば、問題なく使用可能であり、反応に具する一般式（１）または一般式（２）で表される光学活性トリフルオロメチル基含有イミン誘導体に対して、１．０〜１０．０モル量使用する。また、反応の開始前に、亜鉛を活性化する目的で亜鉛に対して０．０１モル量のトリメチルシリルクロリドを亜鉛と溶剤の懸濁液にあらかじめ添加しても良い。 Zinc used in the reaction of the optically active trifluoromethyl group-containing imine derivative represented by the general formula (1) or the general formula (2) obtained in the present invention and the allyl halides represented by the general formula (7) is As long as it is a powder that can be obtained industrially or as a reagent, it can be used without any problem. For the optically active trifluoromethyl group-containing imine derivative represented by the general formula (1) or (2), 1.0 to 10.0 molar amount is used. Further, before the start of the reaction, 0.01 mol of trimethylsilyl chloride with respect to zinc may be added in advance to the suspension of zinc and solvent for the purpose of activating zinc.
本発明で得られた一般式（１）または一般式（２）で表される光学活性トリフルオロメチル基含有イミン誘導体と一般式（７）で表されるアリルハライド類との反応の反応温度及び時間は、反応に用いる溶剤の種類、量及び触媒の種類及び量により異なるが、通常、−４０℃〜４０℃の温度範囲で４〜４８時間反応させることにより反応は完結する。 The reaction temperature of the reaction between the optically active trifluoromethyl group-containing imine derivative represented by the general formula (1) or the general formula (2) obtained in the present invention and the allyl halides represented by the general formula (7); Although the time varies depending on the kind and amount of the solvent used in the reaction and the kind and amount of the catalyst, the reaction is usually completed by reacting in the temperature range of −40 ° C. to 40 ° C. for 4 to 48 hours.
本発明で得られた一般式（１）または一般式（２）で表される光学活性トリフルオロメチル基含有イミン誘導体と一般式（７）で表されるアリルハライド類との反応の後処理としては、公知の方法で可能で、例えば塩化アンモニウム水溶液を添加の後、ジエチルエーテルで抽出、硫酸ナトリウムで乾燥、ろ過、濃縮することにより一般式（８）または一般式（９）で表される環状アミン誘導体を粗製物として得る。さらに、必要に応じてシリカゲルカラムクロマトグラフィーや減圧蒸留等で精製しても良い。 As a post-treatment of the reaction between the optically active trifluoromethyl group-containing imine derivative represented by the general formula (1) or the general formula (2) obtained in the present invention and the allyl halides represented by the general formula (7) Can be obtained by a known method. For example, an aqueous ammonium chloride solution is added, followed by extraction with diethyl ether, drying with sodium sulfate, filtration, and concentration, and the cyclic structure represented by general formula (8) or general formula (9). The amine derivative is obtained as a crude product. Furthermore, you may refine | purify by silica gel column chromatography, vacuum distillation, etc. as needed.
以下実施例により本発明を具体的に説明するが、本発明はこれらの実施例のみに限定されるものではない。
生成物の定量には、ＢＲＵＫＥＲ製ＡＶＡＮＣＥ II ４００（ＮＭＲ）を用い実施した。
EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited only to these examples.
The product was quantified using AVANCE II 400 (NMR) manufactured by BRUKER.
参考例１ （Ｒ）−２−エトキシ−１−フェニルエチル−１−アミンの調製
攪拌子及び滴下ロートを備えた５Ｌの４つ口丸底フラスコに、窒素気流下、水素化ナトリウム（６０％油性，５８．３ｇ，１４５８ｍｍｏｌ）及びＴＨＦ（１Ｌ）を仕込み攪拌した。次いで、これにＴＨＦ（７５０ｍｌ）に溶解させた（Ｒ）−フェニルグルシノール（１００ｇ，７２９ｍｍｏｌ）を室温下、滴下ロートを用い、３０分かけて滴下した。滴下終了後、エチルヨージド（２２７ｇ，１４５５ｍｍｏｌ）を添加し、室温下で１２時間攪拌した。反応終了後、減圧下、溶媒を留去、残渣を水２００ｍｌに溶解させ、酢酸エチル（５０ｍｌ）で４回抽出、得られた有機層を硫酸ナトリウム上で乾燥、ろ過、濃縮、減圧蒸留し、目的物の（Ｒ）−２−エトキシ−１−フェニルエチル−１−アミンを無色油状物として得た（１０２ｇ，６２０ｍｍｏｌ、収率８５％）。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ＝１．１８（ｔ，３Ｈ，Ｊ＝７．０Ｈｚ）、１．９２（ｓ，２Ｈ），３．３４（ｔ，1Ｈ，Ｊ＝９．２Ｈｚ）、３．４０−３．５２（ｍ，3Ｈ），４．１４（ｄｄ，１Ｈ，Ｊ＝９．４，３．８Ｈｚ）、７．１０−７．４５（ｍ，５Ｈ）ｐｐｍ。
Reference Example 1 Preparation of (R) -2-ethoxy-1-phenylethyl-1-amine A 5 L 4-neck round bottom flask equipped with a stirrer and a dropping funnel was charged with sodium hydride (60% oily) under a nitrogen stream. , 58.3 g, 1458 mmol) and THF (1 L) were added and stirred. Next, (R) -phenylglucinol (100 g, 729 mmol) dissolved in THF (750 ml) was added dropwise thereto over 30 minutes at room temperature using a dropping funnel. After completion of the dropwise addition, ethyl iodide (227 g, 1455 mmol) was added and stirred at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 200 ml of water, extracted four times with ethyl acetate (50 ml), and the resulting organic layer was dried over sodium sulfate, filtered, concentrated and distilled under reduced pressure. The desired product (R) -2-ethoxy-1-phenylethyl-1-amine was obtained as a colorless oil (102 g, 620 mmol, yield 85%).
1 H-NMR (400 MHz, CDCl 3) δ = 1.18 (t, 3H, J = 7.0 Hz), 1.92 (s, 2H), 3.34 (t, 1H, J = 9.2 Hz), 3.40-3.52 (m, 3H), 4.14 (dd, 1H, J = 9.4, 3.8 Hz), 7.10-7.45 (m, 5H) ppm.
実施例１ （Ｒ）−トリフルオロメチル ２−エトキシ−１−フェニルエチル−１−イミンの調製
還流コンデンサー、水分離器（ディーン・スターク）、攪拌子及び滴下ロートを備えた５Ｌの四つ口丸底フラスコに、参考例１で調製した（Ｒ）−２−エトキシ−１−フェニルエチル−１−アミン（１０２ｇ，６１７ｍｍｏｌ）、トリフルオロアセトアルデヒド・１水和物（１８２ｇ，１５４３ｍｍｏｌ）、ｐ−トルエンスルホン酸・１水和物（１．２ｇ，６．３ｍｍｏｌ）及びトルエン（１．７Ｌ）を仕込み、オイルバス上で加熱し、還流条件下、共沸で留出する水を除去しながら８時間反応を行った。反応終了後、冷却、濃縮、次いで減圧蒸留することにより目的物の（Ｒ）−トリフルオロメチル ２−エトキシ−１−フェニルエチル−１−イミン（１７０ｇ，純度９５．０％、５１９ｍｍｏｌ，収率８４．１％）を黄色油状物として得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ＝１．１５（ｔ，３Ｈ，Ｊ＝７．０Ｈｚ）、３．４１−３．５４（ｍ，２Ｈ）、３．６１（ｔ，１Ｈ，Ｊ＝９．６Ｈｚ）、３．６９（ｄｄ，１Ｈ，Ｊ＝１０．０，３．６Ｈｚ）、４．５１（ｄｄ，１Ｈ，Ｊ＝９．０，４．０Ｈｚ）、７．２５−７．４１（ｍ，５Ｈ）、７．６８（ｑ，１Ｈ，Ｊ＝３．５Ｈｚ）ｐｐｍ。
１３Ｃ−ＮＭＲ（ＣＤＣｌ３，１００．６ＭＨｚ）δ＝１５．０５、６６．８３、７３．７８、７４．１６、１１９．０１（ｑ，Ｊ＝２７４．８Ｈｚ）、１２７．３５、１２８．３７、１２８．８８、１３８．６８、１５０．１５（ｑ，Ｊ＝３８．０Ｈｚ）ｐｐｍ。
１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ＝−７２．１３（ｄ，Ｊ＝３．８Ｈｚ）ｐｐｍ。
Example 1 Preparation of (R) -trifluoromethyl 2-ethoxy-1-phenylethyl-1-imine A 5 L four-necked round equipped with a reflux condenser, a water separator (Dean Stark), a stir bar and a dropping funnel In the bottom flask, (R) -2-ethoxy-1-phenylethyl-1-amine (102 g, 617 mmol), trifluoroacetaldehyde monohydrate (182 g, 1543 mmol) prepared in Reference Example 1, p-toluenesulfone Acid / monohydrate (1.2 g, 6.3 mmol) and toluene (1.7 L) are charged, heated on an oil bath, and reacted for 8 hours while removing water distilled off azeotropically under reflux conditions. Went. After completion of the reaction, the reaction mixture was cooled, concentrated, and then distilled under reduced pressure to give the desired product (R) -trifluoromethyl 2-ethoxy-1-phenylethyl-1-imine (170 g, purity 95.0%, 519 mmol, yield 84). 0.1%) as a yellow oil.
1 H-NMR (400 MHz, CDCl 3 ) δ = 1.15 (t, 3H, J = 7.0 Hz), 3.41-3.54 (m, 2H), 3.61 (t, 1H, J = 9.6 Hz), 3.69 (dd, 1H, J = 10.0, 3.6 Hz), 4.51 (dd, 1H, J = 9.0, 4.0 Hz), 7.25-7.41. (M, 5H), 7.68 (q, 1H, J = 3.5 Hz) ppm.
13 C-NMR (CDCl 3 , 100.6 MHz) δ = 15.05, 66.83, 73.78, 74.16, 119.01 (q, J = 274.8 Hz), 127.35, 128.37 128.88, 138.68, 150.15 (q, J = 38.0 Hz) ppm.
19 F-NMR (376 MHz, CDCl 3 ) δ = −72.13 (d, J = 3.8 Hz) ppm.
実施例２ （Ｓ）−トリフルオロメチル ２−エトキシ−１−フェニルエチル−１−イミンの調製
参考例１と同じ方法で調製した（Ｓ）−２−エトキシ−１−フェニルエチル−１−アミン（１００ｇ，６０８ｍｍｏｌ）を用い、実施例１と同じ方法で反応を行い、目的物の（Ｓ）−トリフルオロメチル ２−エトキシ−１−フェニルエチル−１−イミン（１７７ｇ，純度９３．２％、５２９ｍｍｏｌ，収率８７．４％）を黄色オイルとして得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ＝１．１５（ｔ，３Ｈ，Ｊ＝７．０Ｈｚ）、３．４１−３．５４（ｍ，２Ｈ）、３．６１（ｔ，１Ｈ，Ｊ＝９．６Ｈｚ）、３．６９（ｄｄ，１Ｈ，Ｊ＝１０．０，３．６Ｈｚ）、４．５１（ｄｄ，１Ｈ，Ｊ＝９．０，４．０Ｈｚ）、７．２５−７．４１（ｍ，５Ｈ）、７．６８（ｑ，１Ｈ，Ｊ＝３．５Ｈｚ）ｐｐｍ。
１３Ｃ−ＮＭＲ（ＣＤＣｌ３，１００．６ＭＨｚ）δ＝１５．０５、６６．８３、７３．７８、７４．１６、１１９．０１（ｑ，Ｊ＝２７４．８Ｈｚ）、１２７．３５、１２８．３７、１２８．８８、１３８．６８、１５０．１５（ｑ，Ｊ＝３８．０Ｈｚ）ｐｐｍ。
１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ＝−７２．１３（ｄ，Ｊ＝３．８Ｈｚ）ｐｐｍ。
Example 2 Preparation of ( S) -trifluoromethyl 2-ethoxy-1-phenylethyl-1-imine (S) -2-ethoxy-1-phenylethyl-1-amine prepared in the same manner as in Reference Example 1 ( 100 g, 608 mmol), and the reaction was carried out in the same manner as in Example 1, and the target product (S) -trifluoromethyl 2-ethoxy-1-phenylethyl-1-imine (177 g, purity 93.2%, 529 mmol) was obtained. Yield 87.4%) as a yellow oil.
1 H-NMR (400 MHz, CDCl 3) δ = 1.15 (t, 3H, J = 7.0 Hz), 3.41-3.54 (m, 2H), 3.61 (t, 1H, J = 9) .6 Hz), 3.69 (dd, 1 H, J = 10.0, 3.6 Hz), 4.51 (dd, 1 H, J = 9.0, 4.0 Hz), 7.25-7.41 ( m, 5H), 7.68 (q, 1H, J = 3.5 Hz) ppm.
13 C-NMR (CDCl 3 , 100.6 MHz) δ = 15.05, 66.83, 73.78, 74.16, 119.01 (q, J = 274.8 Hz), 127.35, 128.37 128.88, 138.68, 150.15 (q, J = 38.0 Hz) ppm.
19 F-NMR (376 MHz, CDCl 3 ) δ = −72.13 (d, J = 3.8 Hz) ppm.
実施例３ （１'Ｒ，４Ｓ）−４−（２'−エトキシ−１'−フェニルエチル−１'−アミノ）−５，５，５−トリフルオロ−１−ペンテンの調製
攪拌子を備えた１０ｍｌの丸底フラスコに、亜鉛粉末（１１０．２ｍｇ，１．６９ｍｍｏｌ）を仕込み、窒素置換した後、これにＮ，Ｎ−ジメチルホルムアミド（４ｍｌ）及びトリメチルシリルクロリド（２滴）を添加し、室温下１０分攪拌した。次いで、氷浴上で０℃に冷却の後、実施例１で調製した（Ｒ）−トリフルオロメチル ２−エトキシ−１−フェニルエチル−１−イミン（３１８．１ｍｇ，１．３０ｍｍｏｌ）及びアリルブロミド（２０４．０ｍｇ，１．６９ｍｍｏｌ）を添加し、同温度で１０分攪拌し、さらに室温下、８時間反応を行った。
反応終了後、ろ過し、不溶物を除去の後、水（１００ｌ）を添加、酢酸エチル（５０ｍｌ）で３回抽出、得られた有機層を合わせて、水（１００ｍｌ）で洗浄、硫酸ナトリウム上で乾燥、ろ過、濃縮することにより目的物を粗製物として得た（５０６．９ｍｇ）。ベンゾトリフルリド内部標準法によるＦ−ＮＭＲの分析で、生成量３１６．８ｍｇ、収率８５％、（１'Ｒ，４Ｓ）体／（１'Ｒ，４Ｒ）体比は９１／９（８２％ｄｅ）であった。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ＝１．０９（ｔ，３Ｈ，Ｊ＝７．０Ｈｚ）、２．１８−２．４０（ｍ，１Ｈ）、２．４０−２．２３（ｍ，１Ｈ）、３．３７−３．７０（ｍ，５Ｈ）、４．０６（ｄｄ，１Ｈ，Ｊ＝９．６，３．６Ｈｚ）、５．１５（ｄ，１Ｈ、Ｊ＝０．８Ｈｚ）、５．１６（ｄｔ，１Ｈ，Ｊ＝２８．０，１．２Ｈｚ），７．１０−７．７０（ｍ，５Ｈ）ｐｐｍ。
Example 3 Preparation of (1′R, 4S) -4- (2′-Ethoxy-1′-phenylethyl-1′-amino) -5,5,5-trifluoro-1-pentene A 10 ml round bottom flask was charged with zinc powder (110.2 mg, 1.69 mmol) and purged with nitrogen, and then N, N-dimethylformamide (4 ml) and trimethylsilyl chloride (2 drops) were added thereto at room temperature. Stir for 10 minutes. Then, after cooling to 0 ° C. on an ice bath, (R) -trifluoromethyl 2-ethoxy-1-phenylethyl-1-imine (318.1 mg, 1.30 mmol) and allyl bromide prepared in Example 1 (204.0 mg, 1.69 mmol) was added, the mixture was stirred at the same temperature for 10 minutes, and further reacted at room temperature for 8 hours.
After completion of the reaction, the mixture was filtered to remove insolubles, water (100 l) was added, extracted three times with ethyl acetate (50 ml), and the resulting organic layers were combined, washed with water (100 ml) and washed with sodium sulfate. The product was obtained as a crude product by drying, filtering and concentrating on (506.9 mg). In the analysis of F-NMR by the benzotrifluoride internal standard method, the production amount was 316.8 mg, the yield was 85%, and the (1′R, 4S) isomer / (1′R, 4R) isomer ratio was 91/9 (82% de).
1 H-NMR (400 MHz, CDCl 3 ) δ = 1.09 (t, 3H, J = 7.0 Hz), 2.18-2.40 (m, 1H), 2.40-2.23 (m, 1H), 3.37-3.70 (m, 5H), 4.06 (dd, 1H, J = 9.6, 3.6 Hz), 5.15 (d, 1H, J = 0.8 Hz), 5.16 (dt, 1H, J = 28.0, 1.2 Hz), 7.10-7.70 (m, 5H) ppm.
実施例４ （１'Ｓ，４Ｒ）−４−（２'−エトキシ−１'−フェニルエチル−１'−アミノ）−５，５，５−トリフルオロ−１−ペンテンの調製
実施例３の（Ｒ）−トリフルオロメチル ２−エトキシ−１−フェニルエチル−１−イミンに替えて（Ｓ）−トリフルオロメチル ２−エトキシ−１−フェニルエチル−１−イミンを用いた以外実施例３と同じ操作を行い、目的物の（１'Ｓ，４Ｒ）−４−（２'−エトキシ−１'−フェニルエチル−１'−アミノ）−５，５，５−トリフルオロ−１−ペンテンを得た。Ｆ−ＮＭＲの分析で、生成量３２４．３ｍｇ、収率８７％、（１'Ｓ，４Ｒ）体／（１'Ｓ，４Ｓ）体比は９０／１０（８０％ｄｅ）であった。
Example 4 Preparation of (1 ′S, 4R) -4- (2′-Ethoxy-1′-phenylethyl-1′-amino) -5,5,5-trifluoro-1-pentene R) -trifluoromethyl 2-ethoxy-1-phenylethyl-1-imine The same procedure as in Example 3 except that (S) -trifluoromethyl 2-ethoxy-1-phenylethyl-1-imine was used. The target product (1 ′S, 4R) -4- (2′-ethoxy-1′-phenylethyl-1′-amino) -5,5,5-trifluoro-1-pentene was obtained. As a result of F-NMR analysis, the production amount was 324.3 mg, the yield was 87%, and the (1 ′S, 4R) isomer / (1 ′S, 4S) isomer ratio was 90/10 (80% de).
比較例１ （Ｒ）−トリフルオロメチル ２−エトキシ−１−フェニルエチル−１−イミンの調製
攪拌子及び滴下ロートを備えた５Ｌの４つ口丸底フラスコに、窒素気流下、水素化ナトリウム（６０％油性，５８．３ｇ，１４５８ｍｍｏｌ）及びＴＨＦ（１Ｌ）を仕込み攪拌した。次いで、これにＴＨＦ（７５０ｍｌ）に溶解させた（Ｒ）−フェニルグルシノール（１００ｇ，７２９ｍｍｏｌ）を室温下、滴下ロートを用い、３０分かけて滴下した。滴下終了後、メチルヨージド（２０７ｇ，１４５５ｍｍｏｌ）を添加し、室温下で１２時間攪拌した。反応終了後、減圧下、溶媒を留去、残渣を水２００ｍｌに溶解させ、酢酸エチル（５０ｍｌ）で４回抽出、得られた有機層を硫酸ナトリウム上で乾燥、ろ過、濃縮、減圧蒸留し、目的物の（Ｒ）−２−メトキシ−１−フェニルエチル−１−アミンを無色油状物として得た（５６ｇ，３７０ｍｍｏｌ、収率５１．０％）。
還流コンデンサー、水分離器（ディーン・スターク）、攪拌子及び滴下ロートを備えた２Ｌの四つ口丸底フラスコに、（Ｒ）−２−メトキシ−１−フェニルエチル−１−アミン（５６ｇ，３７０ｍｍｏｌ）、トリフルオロアセトアルデヒド・１水和物（１０９ｇ，９２６ｍｍｏｌ）、ｐ−トルエンスルホン酸・１水和物（０．７２ｇ，３．８ｍｍｏｌ）及びトルエン（１．０Ｌ）を仕込み、オイルバス上で加熱し、還流条件下、共沸で留出する水を除去しながら８時間反応を行った。反応終了後、冷却、濃縮、次いで減圧蒸留することにより目的物の（Ｒ）−トリフルオロメチル ２−メトキシ−１−フェニルエチル−１−イミン（５８．２ｇ，純度９３．０％、２３４ｍｍｏｌ，収率６３．２％）を黄色油状物として得た。
参考例１及び実施例１で、本発明の２段の反応の収率が７１．５％であったのに対して、３２．２％であった。
Comparative Example 1 Preparation of (R) -trifluoromethyl 2-ethoxy-1-phenylethyl-1-imine A 5 L four-necked round bottom flask equipped with a stirrer and a dropping funnel was charged with sodium hydride ( 60% oily, 58.3 g, 1458 mmol) and THF (1 L) were charged and stirred. Next, (R) -phenylglucinol (100 g, 729 mmol) dissolved in THF (750 ml) was added dropwise thereto over 30 minutes at room temperature using a dropping funnel. After completion of the dropwise addition, methyl iodide (207 g, 1455 mmol) was added and stirred at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 200 ml of water, extracted four times with ethyl acetate (50 ml), and the resulting organic layer was dried over sodium sulfate, filtered, concentrated and distilled under reduced pressure. The desired product (R) -2-methoxy-1-phenylethyl-1-amine was obtained as a colorless oil (56 g, 370 mmol, yield 51.0%).
To a 2 L four-necked round bottom flask equipped with a reflux condenser, water separator (Dean Stark), stir bar and dropping funnel was added (R) -2-methoxy-1-phenylethyl-1-amine (56 g, 370 mmol). ), Trifluoroacetaldehyde monohydrate (109 g, 926 mmol), p-toluenesulfonic acid monohydrate (0.72 g, 3.8 mmol) and toluene (1.0 L) are charged and heated on an oil bath Then, the reaction was carried out for 8 hours under reflux conditions while removing water distilled off azeotropically. After completion of the reaction, the reaction mixture was cooled, concentrated, and then distilled under reduced pressure to obtain (R) -trifluoromethyl 2-methoxy-1-phenylethyl-1-imine (58.2 g, purity 93.0%, 234 mmol, yield). 63.2%) was obtained as a yellow oil.
In Reference Example 1 and Example 1, the yield of the two-stage reaction of the present invention was 71.5%, whereas it was 32.2%.
本発明の新規な光学活性トルフルオロメチル基含有イミン誘導体を用いることにより医農薬でとして有用なトリフルオロメチル基含有光学活性アミン類誘導体を容易に合成することができる。 By using the novel optically active trifluoromethyl group-containing imine derivative of the present invention, it is possible to easily synthesize a trifluoromethyl group-containing optically active amine derivative useful as a medicine or agrochemical.
Claims (3)
または、下記一般式（２）
で表されるトリフルオロメチル基含有イミン誘導体。 The following general formula (1)
Or the following general formula (2)
A trifluoromethyl group-containing imine derivative represented by:
ＣＦ３（ＣＨ２）ｎＣＨＯ （５）
（式中、ｎは０〜２の整数を示す）
で表されるトリフルオロメチル基含有アルデヒドまたは、下記一般式（６）
ＣＦ３（ＣＨ２）ｎＣＨ（ＯＨ）２ （６）
（式中ｎは前記に同じ）
で表されるトリフルオロメチル基含有アルデヒド−水和物を、酸触媒存在下、脱水反応を行うことを特徴とする下記一般式（１）
または下記一般式（２）
で表されるトリフルオロメチル基含有イミン誘導体の製造方法。 Following formula (3)
CF 3 (CH 2 ) n CHO (5)
(In the formula, n represents an integer of 0 to 2)
A trifluoromethyl group-containing aldehyde represented by the following general formula (6)
CF 3 (CH 2) n CH (OH) 2 (6)
(Where n is the same as above)
A trifluoromethyl group-containing aldehyde-hydrate represented by the following general formula (1), which is subjected to a dehydration reaction in the presence of an acid catalyst:
Or the following general formula (2)
The manufacturing method of the trifluoromethyl group containing imine derivative represented by these.
または一般式（２）
で表されるトリフルオロメチル基含有イミン誘導体と下記一般式（７）
で表されるアリルハライド類を亜鉛の存在下に反応させることを特徴とする下記一般式（８）
または下記一般式（９）
で表される含フッ素アミン誘導体の製造方法。 The following general formula (1)
Or general formula (2)
A trifluoromethyl group-containing imine derivative represented by the following general formula (7)
The following general formula (8), characterized in that an allyl halide represented by the formula is reacted in the presence of zinc:
Or the following general formula (9)
The manufacturing method of the fluorine-containing amine derivative represented by these.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005012276A2 (en) * | 2003-07-31 | 2005-02-10 | Centre Nationale De La Recherche Scientifique | Intermediate products of the synthesis of fluorized inhibitors of aspartic proteases |
| JP2005523339A (en) * | 2002-04-16 | 2005-08-04 | ロディア・シミ | Aminated compounds having at least allyl and difluoromethyl and methods used for their synthesis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005523339A (en) * | 2002-04-16 | 2005-08-04 | ロディア・シミ | Aminated compounds having at least allyl and difluoromethyl and methods used for their synthesis |
| WO2005012276A2 (en) * | 2003-07-31 | 2005-02-10 | Centre Nationale De La Recherche Scientifique | Intermediate products of the synthesis of fluorized inhibitors of aspartic proteases |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2013241344A (en) * | 2012-05-18 | 2013-12-05 | Tosoh F-Tech Inc | TRIFLUOROMETHYL GROUP-CONTAINING OPTICALLY ACTIVE β-AMINO ACID DERIVATIVE AND METHOD FOR PRODUCING THE SAME |
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