JP5158926B2 - Method for producing chiral zirconium catalyst for asymmetric Mannich type reaction - Google Patents

Description

The present invention is related to method for producing a highly stable key manufacturing method Lal zirconium catalyst, and the resulting β- aminocarbonyl compound in the optically active a chiral zirconium catalyst for the asymmetric Mannich reaction.

Conventionally, chiral zirconium catalysts and reactions using the catalysts are known, for example, from Patent Documents 1 to 11 and documents described in these patent documents.
Japanese Patent Laid-Open No. 11-33407 Japanese Patent Laid-Open No. 11-253813 JP 2001-252568 A Japanese Patent Laid-Open No. 2001-252569 JP 2002-201166 JP JP 2002-356454 JP JP 2003-261490 A Japanese Patent Laid-Open No. 2003-299962 JP 2006-22046 A International Patent Application Publication No. 03/076072 Pamphlet International Patent Application Publication No. 2005/084803 Pamphlet

However, the zirconium complex in the conventional chiral zirconium catalyst is unstable in the air or requires a technique such as polymer immobilization for stabilization.
The present invention has been made in view of such circumstances, enantiomeric and β- aminocarbonyl compound in the optically active by using a very stable key Lal zirconium catalyst, and the resulting chiral zirconium catalyst for the asymmetric Mannich reaction It is an object to provide a method for manufacturing with high selectivity.

The present inventor has proceeded with extensive research to solve the above problems, which has led to the completion of the present invention, the present invention is Ru der those summarized as following [1] to [7].

（式中、Ｘ¹およびＸ²は、同一または別異に水素原子、ハロゲン原子またはフッ素化炭化水素基であり、Ｘ¹およびＸ²のいずれか一方はハロゲン原子またはフッ素化炭化水素基である。）で表されるビナフトール化合物と、Ｎ−アルキルイミダゾールまたはN−ベンジルイミダゾールと、を混合し反応させて得られる粉末を、水を含む有機溶媒中で結晶化させることを特徴とする不斉マンニッヒ型反応用キラルジルコニウム触媒の製造方法。 [ 1 ] Zr (OR) ₄ (where R is a linear or branched alkyl group) and

(In the formula, X ¹ and X ² are the same or different and are a hydrogen atom, a halogen atom or a fluorinated hydrocarbon group, and one of X ¹ and X ² is a halogen atom or a fluorinated hydrocarbon group. . and binaphthol compounds represented by), N- alkyl imidazole or N- benzyl imidazole, a powder obtained mixture by reacting, characterized by the Turkey is crystallized in an organic solvent containing water- Process for producing chiral zirconium catalyst for simultaneous Mannich type reaction .

[2] Zr (OR) ₄ The production method according to claim 1, wherein the binaphthol compound is reacted in an amount of 150 to 300 parts by weight and the imidazole is mixed in an amount of 100 to 400 parts by weight with respect to 100 parts by weight.
[3] The production method according to claim 1 or 2, wherein the organic solvent contains 10 to 1000 ppm of water.

[4] The binaphthol compound, (R) -6,6 '- process according to any one of claims 1 to 3 is a dibromo-1,1'-bis-2-naphthol.
[5] A process for producing an optically active β-aminocarbonyl compound in which imine and silicon enolate are reacted in the presence of the chiral zirconium catalyst obtained by the process according to any one of claims 1 to 4.

（式中、Ｒ¹は置換基を有していてもよい炭化水素基または置換基を有していてもよい芳香族基を表し、Ｒ²は水素原子または置換基を有していてもよい炭化水素基を表す。）で表されるイミンである、請求項５に記載の光学活性β−アミノカルボニル化合物の製造方法。
〔７〕ケイ素エノラートが、イソ酪酸由来のケイ素エノラートである、請求項５に記載の光学活性β−アミノカルボニル化合物の製造方法。 [6] The imine has the following formula (II)

(In the formula, R ¹ represents a hydrocarbon group which may have a substituent or an aromatic group which may have a substituent, and R ² may have a hydrogen atom or a substituent. The method for producing an optically active β-aminocarbonyl compound according to claim 5, which is an imine represented by a hydrocarbon group.
[7] The process for producing an optically active β-aminocarbonyl compound according to claim 5, wherein the silicon enolate is a silicon enolate derived from isobutyric acid.

The present invention can be handled stably even in air, very process for producing a stable key Lal zirconium catalyst for the asymmetric Mannich reaction, and the resulting a chiral zirconium catalyst, an optically active β- amino carbonyl compounds, A method for producing with high enantioselectivity is provided.

The chiral zirconium catalyst (I) of the present invention comprises Zr (OR) ₄ (wherein R is a linear or branched alkyl group), (R) -6,6′-Br ₂ BINOL, N— It can be obtained by recrystallizing a powder obtained by mixing alkylimidazole or N-benzylimidazole (hereinafter also collectively referred to as imidazole) in an organic solvent containing water.

  Examples of the organic solvent include aromatic hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as carbon tetrachloride, chloroform, and 1,2-dichloroethane; ethers such as diethyl ether, diisopropyl ether, dioxane, and tetrahydrofuran. Ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; nitriles such as acetonitrile and propionitrile; carboxylic acid esters such as ethyl acetate and ethyl propionate; N, N-dimethylformamide, N, N-dimethylacetamide; Nitrogen-containing aprotic polar solvents such as N-methyl-2-pyrrolidone and 1,3-dimethyl-2-imidazolidinone; sulfur-containing aprotic polar solvents such as dimethyl sulfoxide and sulfolane; or a mixed solvent thereof It is done. Among these, aromatic hydrocarbons or carboxylic acid esters are preferable, and toluene or ethyl acetate is particularly preferable from the viewpoints of solubility and economy.

  It is essential that the organic solvent contains water. The content of water in the organic solvent is preferably 10 to 1000 ppm, particularly preferably 20 to 100 ppm. Therefore, the content of water in the organic solvent may be such that it contains moisture in the air. For this reason, molecular sieves containing water may coexist.

Examples of the recrystallization method include Zr (OR) ₄ (wherein R is a linear or branched alkyl group) and

で表される化合物、例えば、(R)-6,6'-Br₂BINOLと、Ｎ−アルキルイミダゾールまたはN−ベンジルイミダゾールとを混合して得られた粉末を、室温で飽和する程度の有機溶媒中に溶解し、有機溶媒を自然に蒸発させながら徐々に結晶を析出させるか、または、ヘキサン等の貧溶媒の蒸気に曝露させながら結晶を徐々に析出させるといった方法が好ましい。

An organic solvent that saturates a powder obtained by mixing (R) -6,6′-Br ₂ BINOL with N-alkylimidazole or N-benzylimidazole at room temperature A method in which the crystal is gradually dissolved while being dissolved in the organic solvent and the organic solvent is naturally evaporated, or the crystal is gradually precipitated while being exposed to a vapor of a poor solvent such as hexane is preferable.

In the present invention, each content ratio in the mixed powder of Zr (OR) ₄ , (R) -6,6′-Br ₂ BINOL, and imidazole is based on 100 parts by weight of Zr (OR) ₄ . (R) -6,6′-Br ₂ BINOL is preferably 150 to 300 parts by weight, particularly preferably 200 to 220 parts by weight, and imidazole is preferably 100 to 400 parts by weight, particularly preferably 120 to 220 parts by weight. It is appropriate.

In the present invention, the presence of the chiral zirconium catalyst, Ri by an imine and a silicon enolate to be Mannich-type reaction, optically active β- amino carbonyl compounds can be produced.

  In such a method for producing an optically active β-aminocarbonyl compound, various types of imines are used. Among them, the following formula (II)

で表される化合物が好ましい。

The compound represented by these is preferable.

In the above formula (II), R ¹ is appropriately selected from a hydrocarbon group which may have a substituent or an aromatic group which may have a substituent. Among them, a phenyl group, a substituted phenyl group, a naphthyl group, a substituted naphthyl group, an alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, a cyclohexyl group, or the like is preferable. Illustrated. R ² is a hydrogen atom or a hydrocarbon group which may have a substituent, and alkyl such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and the like. Examples are groups. R ¹ and R ² are appropriately selected depending on the product of the desired Mannich type reaction, that is, the optically active anti-α-methyl-β-aminocarbonyl compound.

  In addition, as such an imine, a compound that has been used as a reagent or a compound that has been synthesized, purified, and isolated in advance may be used. For those that are difficult to isolate or unstable, a Mannich-type reaction may be used. You may synthesize | combine and use in situ.

  In the method for producing an optically active β-aminocarbonyl compound of the present invention, the Mannich type reaction is performed in the presence of the novel chiral zirconium catalyst, but the reaction conditions are not particularly limited. For example, the reaction is preferably performed in various organic solvents. The organic solvent is not particularly limited as long as it can dissolve the imine as the starting material, the silicon enolate as the nucleophile, and the catalyst, and does not solidify or decompose at the reaction temperature. Examples include halogenated hydrocarbons such as chloroform and dichloromethane, acetone and the like. The reaction temperature may be a temperature range in which each reactant is stable and the catalyst acts stably, and is preferably a temperature range below room temperature, more preferably about −100 ° C. to room temperature. Furthermore, for specific reaction operations, operations such as stirring, separation, and purification performed in general chemical reactions can be applied.

  Hereinafter, the present invention will be described in more detail with reference to examples. Of course, it goes without saying that the present invention is not construed as being limited to the following examples.

In the following examples, the melting point is displayed without correction. ¹ H and ¹³ C NMR spectra were measured in CDCl _{3 using} a JEOL JNM-LA300, JNM-LA400, or JNM-LA500 spectrometer unless otherwise specified. In 1H, tetramethylsilane (TMS) was used as an internal standard (δ = 0). For ¹³ C, CDCl ₃ was used as an internal standard (δ = 77.0).

  High performance liquid chromatography was performed using SHIMADZU LC-10AT (liquid chromatograph), SHIMADZU SPD-10A (ultraviolet detector), and SHIMADZU C-R6A or C-R8A chromatopack.

  Column chromatography was performed using Silica gel 60 (Merck), and thin layer chromatography was performed using Wakogel B-5F (Wako Pure Chemical Industries).

For dichloromethane, a dehydrated product manufactured by Kanto Chemical Co. was distilled over CaH ₂ and further dried over MS 4A. Other solvents and compounds were used after purification by standard methods.

  Aromatic aldehydes, and aldimines of heteroaromatic aldehydes, were prepared by conventional methods using the corresponding aldehyde and 2-aminophenol. The crude aldimine was recrystallized from ethanol to obtain a pure substance. Ketene silyl acetals were prepared by known methods (Ireland, R.E .; Mueller, R.H .; Willard, A.K.J.Am.Chem.Soc. 1976, 98, 2826).

Example 1 Synthesis of Chiral Zirconium Catalyst In a glove box, (R) -6,6′-dibromo-1,1′-bi-2-naphthol ((R) -6,6′-Br ₂ BINOL) (1.00 mmol), Zr (OiPr) ₄ (0.50 mmol), and N-benzylimidazole (1.00 mmol) were mixed, dichloromethane (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. To this reaction solution was added hexane (100 mL) dried with molecular sieves and stirred at room temperature overnight. The resulting white precipitate was isolated by filtration and dried under reduced pressure. The obtained white powder was dissolved in ethyl acetate containing water and allowed to stand in the dark, thereby obtaining the target chiral zirconium catalyst having a cubic crystal form.

<Example 2> Mannich reaction of ketene silyl acetal and imine (1) First, according to the following formula, imine (2) and ketene silyl acetal (3) are reacted in the presence of a chiral zirconium catalyst (10 mol%). It was.

The zirconium catalyst (0.01 mmol) obtained in Example 1 above was suspended in dichloromethane, and then a dichloromethane solution of a mixture of compound 2 (0.4 mmol) and 3 (E) (0.48 mmol) at −45 ° C. Was added and stirred at −45 ° C. for 48 hours, and hexane was added to stop the reaction. To the filtrate obtained by removing the catalyst by filtration, a 1N hydrochloric acid / tetrahydrofuran mixed solution was added under ice-cooling, and the mixture was stirred for 1 hour, and then sodium bicarbonate water was added to neutralize the reaction solution. The crude product extracted with ethyl acetate was separated by silica gel chromatography to give compound 4. The optical purity was determined by HPLC analysis using a chiral column.
The yield of compound 4 and optical purity (ee) are shown in Table 1 (Reaction 1).

（２）触媒量を0.02 mmolとし、（１）と同様の方法で化合物4を得た。化合物4aの収率、および光学純度（ee）を表１に示した（反応２）。
（３）触媒量を0.01 mmolとし、N-メチルイミダゾール（0.08 mmol）を共存させて、撹拌時間を２４時間として（１）と同様の方法で化合物4を得た。化合物4の収率、および光学純度（ee）を表１に示した（反応３）。
（４）触媒量を0.01 mmolとし、N-メチルイミダゾール（0.08 mmol）を共存させて、（１）と同様の方法で化合物4を得た。化合物4の収率、および光学純度（ee）を表１に示した（反応４）。

(2) The amount of catalyst was 0.02 mmol, and compound 4 was obtained in the same manner as (1). The yield of compound 4a and the optical purity (ee) are shown in Table 1 (Reaction 2).
(3) The amount of catalyst was 0.01 mmol, N-methylimidazole (0.08 mmol) was allowed to coexist, and the stirring time was 24 hours to obtain Compound 4 in the same manner as (1). The yield of compound 4 and the optical purity (ee) are shown in Table 1 (Reaction 3).
(4) The amount of catalyst was 0.01 mmol, and N-methylimidazole (0.08 mmol) was allowed to coexist to give compound 4 in the same manner as (1). The yield and optical purity (ee) of Compound 4 are shown in Table 1 (Reaction 4).

The chiral zirconium catalyst obtained by the production method of the present invention can be handled stably even in air and is suitable for practical applications. For this reason, by using the chiral zirconium catalyst obtained in the present invention , an optically active β-aminocarbonyl compound is produced with high enantioselectivity. The obtained optically active β-aminocarbonyl compound is an important intermediate in the synthesis of various natural substances and physiologically active substances, and is highly useful.

Claims (7)

Zr (OR) ₄ (where R is a linear or branched alkyl group) and

(In the formula, X ¹ and X ² are the same or different and are a hydrogen atom, a halogen atom or a fluorinated hydrocarbon group, and one of X ¹ and X ² is a halogen atom or a fluorinated hydrocarbon group. . and binaphthol compounds represented by), N- alkyl imidazole or N- benzyl imidazole, a powder obtained mixture by reacting, characterized by the Turkey is crystallized in an organic solvent containing water- Process for producing chiral zirconium catalyst for simultaneous Mannich type reaction . Zr (OR) ₄ The production method according to claim 1, wherein the binaphthol compound is reacted in an amount of 150 to 300 parts by weight and the imidazole is mixed in an amount of 100 to 400 parts by weight with respect to 100 parts by weight. The manufacturing method of Claim 1 or 2 in which the said organic solvent contains 10-1000 ppm of water. The binaphthol compound is, (R) -6,6 '- process according to any one of claims 1 to 3 is a dibromo-1,1'-bis-2-naphthol. The manufacturing method of the optically active (beta) -aminocarbonyl compound which makes imine and silicon enolate react in presence of the chiral zirconium catalyst obtained by the manufacturing method in any one of Claims 1-4. Imine has the following formula (II)

(In the formula, R ¹ represents a hydrocarbon group which may have a substituent or an aromatic group which may have a substituent, and R ² may have a hydrogen atom or a substituent. The method for producing an optically active β-aminocarbonyl compound according to claim 5, which is an imine represented by a hydrocarbon group.   The method for producing an optically active β-aminocarbonyl compound according to claim 5, wherein the silicon enolate is a silicon enolate derived from isobutyric acid.