JP4643474B2 - Method for producing mono-substituted succinimide - Google Patents

Description

  The present invention relates to a process for producing monosubstituted succinimides useful as intermediates for antitumor substances and the like.

  Monosubstituted succinimide compounds substituted at the 2-position are often used as useful synthetic intermediates for pharmaceuticals such as antitumor substances and biologically active substances.

The 1,4-addition reaction to a maleimide compound (Non-patent Document 1) is considered to be a useful technique for the production of a succinimide compound, but there are very few reported examples of a method for producing a succinimide compound using this reaction. The current situation is limited, and development of an effective method for producing succinimide is underway.
Jason K. Myers, Eric N. Jacobsen, J. Am. Chem. Soc. 1999, 121, 8959-8960.

  An object of the present invention is to provide a new method for easily and efficiently producing a succinimide compound based on a maleimide compound.

  The present inventors paid attention to various nucleophilic reactions with silicon enolate using a Lewis acid catalyst, and developed an efficient synthesis method of monosubstituted succinimide compounds by 1,4-addition reaction of silicon enolate and maleimide compounds. As a result, a search for a catalyst was conducted to find that a protonic acid or metal triflate containing a trifluoromethanesulfonate structure was effective as a catalyst, and the following inventions were completed.

（Ｒ^１は水素原子または炭素数１〜１０の炭化水素基、複素環基又はベンゾイルアミノ基を示す）；
式（II）で表されるケイ素エノラートを、
式（II）

（式中のＲ^２及びＲ^３はそれぞれ別異に水素原子、アルコキシ基、トリアルキルシリルオキシ基または置換基を有していても良い炭素数１〜１０の炭化水素基又はヘテロ環基を示し、Ｒ^２又はＲ^３の一方がアルコキシ基又はアルコキシシリル基の場合は他方は水素原子又は炭化水素基であり、Ｒ^４は炭素数１〜１０の炭化水素基、アルコキシ基、アルキルチオ基又はアリールチオ基を示し、Ｒ^５は炭素数１〜６のそれぞれが同じでも異なっていても良い炭化水素基を示す）；
トリフルオロメタンスルホン酸、トリフルオロメタンスルホンイミド又は金属トリフラートを触媒として反応させることを含む、式（III）で表される１置換コハク酸イミド化合物の製造方法。 (1) a maleimide compound represented by the formula (I);
Formula (I)

(R ¹ represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, a heterocyclic group or a benzoylamino group);
A silicon enolate represented by the formula (II)
Formula (II)

(In the formula, R ² and R ³ are each independently a hydrogen atom, an alkoxy group, a trialkylsilyloxy group, or a C 1-10 hydrocarbon group or heterocyclic group which may have a substituent. , R ² or R ³ is an alkoxy group or an alkoxysilyl group, the other is a hydrogen atom or a hydrocarbon group, and R ⁴ is a hydrocarbon group having 1 to 10 carbon atoms, an alkoxy group, an alkylthio group, or an arylthio group. And R ⁵ represents a hydrocarbon group having 1 to 6 carbon atoms, which may be the same or different.
A method for producing a monosubstituted succinimide compound represented by the formula (III), which comprises reacting trifluoromethanesulfonic acid, trifluoromethanesulfonimide or metal triflate as a catalyst.

（Ｒ^１〜Ｒ^４は前記と同義である）
（２）金属トリフラートが希土類金属トリフラート又はハフニウムトリフラートのいずれか１種である、（１）に記載の製造方法。 Formula (III)

(R ^{1 to} R ⁴ are as defined above)
(2) The production method according to (1), wherein the metal triflate is any one of rare earth metal triflate and hafnium triflate.

(3) A monosubstituted succinimide represented by the formula (IV) using a silicon enolate in which one of R ² and R ^{3 in} the formula (II) is a hydrogen atom and the other is a substituent other than a hydrogen atom The production method according to (1) or (2), wherein one of the diastereomers and a symmetric product thereof are selectively produced.

Formula (IV)

  The present invention can produce monosubstituted succinamides useful as various intermediates by a simple method. In addition, the reaction can be carried out under relatively mild conditions such that the reaction can be carried out at around 0 ° C.

Moreover, when 1-substituted silicon enolate in which R ² and R ³ are different from each other is used as the silicon enolate represented by the formula (II), the reaction can also be carried out with high diastereoselectivity.

  The maleimide compound used in the present invention is a compound having a structure represented by the following formula (I).

ここで、式中のＲ^１は水素原子または炭素数１〜１０の炭化水素基、複素環基又はベンゾイルアミノ基を示す。 Formula (I)

Here, R ¹ in the formula is a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, heterocyclic group or benzoylamino group.

  The hydrocarbon group having 1 to 10 carbon atoms is a linear or branched alkyl group (for example, methyl group, ethyl group, propyl group, i-propyl group, butyl group, etc.), alkenyl group (for example, ethenyl group, 1- Propenyl group, 2-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group or 2-pentenyl group), alkynyl group (for example, 2-propynyl group, 2-butynyl group, 3- Butynyl group etc.), cycloalkyl group (eg cyclobutyl group, cyclopentyl group or cyclohexyl group), cycloalkylalkyl group (eg cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group etc.) or aryl such as phenyl group or naphthyl group Group, or aralkyl group such as benzyl group or phenethyl group Door can be. Examples of the heterocyclic group include a 4-pyridyl group, a 2-thienyl group, a 3-furyl group, and a 3-indolyl group.

  Such a maleimide compound can be appropriately prepared by those skilled in the art from maleic anhydride and an amine compound, and a commercially available compound may be used.

  The silicon enolate used in the present invention is a compound having a structure represented by the following formula (II).

ここで、式中のＲ^２及びＲ^３は、それぞれ水素原子、アルコキシ基、トリアルキルシリルオキシ基または置換基を有していても良い炭素数１〜１０の炭化水素基又はヘテロ環基を示し、Ｒ^２及びＲ^３は互いに同じあるいは異なっていてもよく、ただしＲ^２又はＲ^３の一方がアルコキシ基又はトリアルキルシリルオキシ基の場合は他方は水素原子又は炭化水素基であり、Ｒ^４は炭素数１〜１０の炭化水素基、アルコキシ基、アルキルチオ基又はアリールチオ基を示し、Ｒ^５は炭素数１〜６の炭化水素基を示す。 Formula (II)

Here, R ² and R ³ in the formula each represent a hydrogen atom, an alkoxy group, a trialkylsilyloxy group or a hydrocarbon group having 1 to 10 carbon atoms or a heterocyclic group which may have a substituent. , R ² and R ³ may be the same or different from each other, provided that when one of R ² or R ³ is an alkoxy group or a trialkylsilyloxy group, the other is a hydrogen atom or a hydrocarbon group, and R ⁴ is A hydrocarbon group having 1 to 10 carbon atoms, an alkoxy group, an alkylthio group or an arylthio group is shown, and R ⁵ is a hydrocarbon group having 1 to 6 carbon atoms.

  Alkoxy group means (alkyl) -O- group, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, tert-butoxy group, n-butoxy group, sec-butoxy group, isobutoxy group, n- A hexyloxy group, an n-octyloxy group, a benzyloxy group, and the like can be given. As a trialkylsilyloxy group, a tert-butyldimethylsilyloxy group and the like can be given.

  The hydrocarbon group which may have a substituent is an unsubstituted hydrocarbon group, or a halogen, carboxyl group, hydroxyl group, alkyl group, ester group, ether group, amino group, heterocyclic group, cyano group, nitro group. It means a hydrocarbon group which may have one or more substituents such as. Here, the hydrocarbon group has the same definition as in the maleimide compound.

  A heterocyclic group is a 5- to 7-membered cyclic substituent containing one or more heteroatoms selected from N, O or S. For example, a pyridyl group, pyrimidinyl group, pyrazinyl group, furyl group, thienyl group, pyrrolyl group , Isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, quinolyl, isoquinolyl, quinazolinyl, benzofuryl, benzothienyl, indolyl, benzoisoxazolyl, benzox Zolyl group, benzoisothiazolyl group, benzothiazolyl group, benzimidazolyl group, benzotriazolyl group, benzothiadiazolyl group, pyrazolopyrimidinyl group, triazolopyrimidinyl group, purinyl group, tetrahydrofuryl group, tetrahydropyranyl group, Pyrrolidinyl group or piperi It may be exemplified sulfonyl groups and the like. These rings may form a condensed ring structure with other rings such as a benzene ring.

  The alkylthio group represents a group in which the above alkyl group is bonded to a sulfur atom, and examples thereof include a methylthio group, an ethylthio group, and a cyclohexylthio group, and the arylthio group includes a phenylthio group.

  Such a silicon enolate can be appropriately prepared by those skilled in the art, and those commercially available as synthesized compounds may be used.

  In the present invention, the maleimide compound and the silicon enolate are reacted using either a trifluoromethanesulfonic acid or trifluoromethanesulfonimide as a protonic acid or a metal triflate as a catalyst, and the compound represented by the formula (III) is reacted. It is a manufacturing method.

この構造式から明らかなように、式（II）のケイ素エノラートにおいてＲ^２及びＲ^３を互いに異なる基とすることで、生成物であるコハク酸イミドにはジアステレオ異性体が生じる。 Formula (III)

As is apparent from this structural formula, diastereoisomers are formed in the product succinimide by making R ² and R ³ different from each other in the silicon enolate of formula (II).

  As the Lewis acid usable in the present invention, it is preferable to use a metal triflate.

Examples of the metal triflate that can be used include Hf (OTf) 4, Yb (OTf) ₃ , Sc (OTf) ₃ , Bi (OTf) ₃ , Cu (OTf) _{2, and the} like. In particular, use of rare earth metal triflate or hafnium triflate is preferable.

  In the 1,4-addition reaction to the maleimide compound in the presence of the above protonic acid or Lewis acid, the reaction proceeds at −78 ° C. to room temperature, although the reaction temperature depends on the type of catalyst.

  Moreover, what is necessary is just to add about 1.0-3.0 equivalent of silicon enolate with respect to 1 equivalent of maleimide compounds, as for the mixing ratio of a maleimide compound and silicon enolate.

  Moreover, the mixing amount of the trifluoromethanesulfonic acid or trifluoromethanesulfonimide which is a catalyst should just mix trifluoromethanesulfonic acid or trifluoromethanesulfonimide in 1-20 mol% with respect to 1 equivalent of maleimide compounds.

  Similarly, the mixing amount of the Lewis acid, particularly the metal triflate, may be mixed in the range of 1 to 20 mol% with respect to 1 equivalent of the maleimide compound.

  By the above method, a monosubstituted succinimide can be produced from a maleimide compound and a silicon enolate compound.

  EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to these examples.

アルゴン雰囲気下、マレイミド(アルドリッチ、38.8 mg, 0.40 mmol)及びHf(OTf)_４(アルドリッチ、15.5 mg, 0.02 mmol)のアセトニトリル(1.0 ml)溶液を−２０℃で撹拌しながら、（１−（エチルチオ）ビニルオキシ）トリメチルシラン(105.8 mg, 0.6 mmol)のアセトニトリル(1.0 ml) 溶液を加え、18時間撹拌した。反応液に水を加えて反応を停止し、塩化メチレンで二度抽出した。有機相を合わせて無水硫酸ナトリウムで乾燥した後、乾燥剤を濾別した。減圧濃縮した後、分取用シリカゲル薄層クロマトグラフィー（ヘキサン：酢酸エチル＝１：１）にて精製し、目的の1,4-付加体を収率８６％で得た(69.2 mg)。

Under an argon atmosphere, a solution of maleimide (Aldrich, 38.8 mg, 0.40 mmol) and Hf (OTf) ₄ (Aldrich, 15.5 mg, 0.02 mmol) in acetonitrile (1.0 ml) was stirred at −20 ° C. with (1- (ethylthio). ) A solution of vinyloxy) trimethylsilane (105.8 mg, 0.6 mmol) in acetonitrile (1.0 ml) was added and stirred for 18 hours. Water was added to the reaction solution to stop the reaction, and the mixture was extracted twice with methylene chloride. The organic phases were combined and dried over anhydrous sodium sulfate, and then the desiccant was filtered off. After concentration under reduced pressure, purification by preparative silica gel thin layer chromatography (hexane: ethyl acetate = 1: 1) gave the desired 1,4-adduct in a yield of 86% (69.2 mg).

S-ethyl 2- (2,5-dioxopyrrolidin-3-yl) ethanethioate: ¹ H NMR (CDCl ₃ ) δ 1.20 (t, 3H, J = 7.3 Hz), 2.47 (dd, 1H, J = 5.5 , 18.3 Hz), 2.83-2.97 (m, 4H), 3.07-3.16 (m, 2H) ¹³ C NMR (CDCl ₃ ) δ 14.5, 23.5, 35.1, 37.7, 43.1, 176.8, 179.4, 196.9.

Table 1 shows the yield of the production method of the present invention when the catalyst, reaction temperature, and reaction time were changed under the above conditions.

実施例１において、触媒をＨｆ（ＯＴｆ）_４とし、式（II）のケイ素エノラートの置換基においてＲ^２及びＲ^３を互いに異なる基としてコハク酸イミドのジアステレオ異性体を製造した結果を表２に示す。

In Example 1, the catalyst was Hf (OTf) ₄ and the diastereoisomers of succinimide were prepared using R ² and R ³ different from each other in the substituent of the silicon enolate of formula (II). Shown in

実施例１において、触媒をＨｆ（ＯＴｆ）_４とし、式（II）のケイ素エノラートの置換基においてＲ^２及びＲ^３を互いに同じ基としてコハク酸イミドを製造した結果を表３に示す。

In Example 1, the catalyst was Hf (OTf) _4, and the results of producing succinimide with R ² and R ³ as the same group in the silicon enolate substituent of formula (II) are shown in Table 3.

Claims (2)

A maleimide compound represented by formula (I);
Formula (I)

(R ¹ represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, a heterocyclic group or a benzoylamino group);
A silicon enolate represented by the formula (II)
Formula (II)

(In the formula, R ² and R ³ are each independently a hydrogen atom, an alkoxy group, a trialkylsilyloxy group, or a C 1-10 hydrocarbon group or heterocyclic group which may have a substituent. , R ² or R ³ is an alkoxy group or an alkoxysilyl group, the other is a hydrogen atom or a hydrocarbon group, and R ⁴ is a hydrocarbon group having 1 to 10 carbon atoms, an alkoxy group, an alkylthio group, or an arylthio group. And R ⁵ represents a hydrocarbon group having 1 to 6 carbon atoms, which may be the same or different.
A method for producing a monosubstituted succinimide compound represented by the formula (III), which comprises reacting trifluoromethanesulfonic acid, trifluoromethanesulfonimide , bismuth triflate or hafnium triflate as a catalyst.
Formula (III)

(R ^{1 to} R ⁴ are as defined above) One of the monosubstituted succinimides represented by the formula (IV) is obtained by using a silicon enolate in which one of R ² and R ³ in the formula (II) is a hydrogen atom and the other is a substituent other than a hydrogen atom. diastereomers and selective production of its antipode, the manufacturing method according to claim 1.
Formula (IV)