JP2011068587A - New aminoalcohol derivative salt, asymmetric organic molecule catalyst having aminoalcohol derivative salt structure and method for producing optically active compound with the asymmetric organic molecule catalyst - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new aminoalcohol derivative salt, to provide an asymmetric organic molecule catalyst having an aminoalcohol derivative salt structure, and to provide a method for producing an optically active compound with the asymmetric organic molecule catalyst. <P>SOLUTION: There is provided an asymmetric organic molecule catalyst represented by formula (1) [wherein, R<SP>1</SP>is an alkyl or aryl; R<SP>2</SP>, R<SP>3</SP>are each independently H or aryl; R<SP>4</SP>is H or a monovalent substituent; R<SP>5</SP>is H or alkyl; X is an organic acid which forms a salt with an aminoalcohol derivative skeleton in formula (1)]. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a novel amino alcohol derivative salt, an asymmetric organic molecular catalyst having an amino alcohol derivative salt structure, and a method for producing an optically active compound using the asymmetric organic molecular catalyst.

  Many biologically relevant compounds such as pharmaceuticals contain asymmetric centers, and the two possible enantiomers often exhibit different actions on the living body. Therefore, it is important to develop an asymmetric synthesis reaction to selectively obtain only one enantiomer.

  Catalytic asymmetric synthesis, which is an advanced process capable of supplying infinite optically active compounds in principle with a very small amount of catalyst, is important for modern organic synthetic chemistry from the viewpoint of energy saving and environmental harmony. This is one of the major research topics. As an asymmetric catalyst, many organometallic catalysts have been developed, but there are also problems that it is expensive and it is difficult to remove the remaining metal. For this reason, in recent years, researches on organic molecular catalysis using an organic molecule containing no metal as a catalyst have been actively conducted for reasons such as low cost, safety, and low environmental burden.

  For example, in Patent Document 1 and Non-Patent Document 1, isoquinuclidine derivatives, which are key synthesis intermediates of various physiologically active compounds such as Tamiflu, are synthesized by an asymmetric Diels-Alder reaction using a Macmillan catalyst, which is an organic molecular catalyst. It is disclosed to synthesize.

JP 2008-50336 A

Angew. Chem. Int. Ed. 46, 5734-5736, 2007

  However, the chemical yield of the isoquinuclidine derivative obtained in Patent Document 1 or Non-Patent Document 1 is low, and optical purity is improved by recrystallization in a later step, but the chemical yield is further reduced. In addition, since the polymer is also produced, it is not easy to separate and purify the product. Therefore, an asymmetric organic molecular catalyst capable of obtaining a target product with high chemical yield and high optical yield is demanded.

  Therefore, the present invention provides a novel asymmetric organic molecular catalyst that can be produced at a low cost and can obtain a target product with a high chemical yield and a high optical yield, and an optically active compound using the asymmetric organic molecular catalyst It is an object to provide a manufacturing method.

  As a result of intensive studies, the present inventors have found that a salt of an amino alcohol derivative having a specific structure is useful as an asymmetric organic molecular catalyst, and has completed the present invention.

  Thus, the first aspect of the present invention provides an amino alcohol derivative salt represented by the following formula (1) to solve the above problems.

（式（１）中、Ｒ^１はアルキル基、又は、置換又は無置換のフェニル基であり、Ｒ^２及びＲ^３は互いに同じ置換基である置換又は無置換のフェニル基であり、Ｒ^４は水素原子又は一価の置換基であり、Ｒ^５は水素原子又はアルキル基であり、Ｘは式（１）中のアミノアルコール誘導体骨格と塩を形成する有機酸を表わす。）

(In Formula (1), R ¹ is an alkyl group or a substituted or unsubstituted phenyl group, R ² and R ³ are substituted or unsubstituted phenyl groups which are the same substituents, and R ⁴ is A hydrogen atom or a monovalent substituent, R ⁵ is a hydrogen atom or an alkyl group, and X represents an organic acid that forms a salt with the amino alcohol derivative skeleton in formula (1).

  The second aspect of the present invention provides an asymmetric organic molecular catalyst represented by the following formula (1) to solve the above problems.

（式（１）中、Ｒ^１はアルキル基又はアリール基であり、Ｒ^２、Ｒ^３はそれぞれ独立に水素原子又はアリール基であり、Ｒ^４は水素原子又は一価の置換基であり、Ｒ^５は水素原子又はアルキル基であり、Ｘは式（１）中のアミノアルコール誘導体骨格と塩を形成する有機酸を表わす。）

(In Formula (1), R ¹ is an alkyl group or an aryl group, R ² and R ³ are each independently a hydrogen atom or an aryl group, R ⁴ is a hydrogen atom or a monovalent substituent, ⁵ is a hydrogen atom or an alkyl group, and X represents an organic acid that forms a salt with the amino alcohol derivative skeleton in formula (1).

  According to a third aspect of the present invention, there is provided an optically active compound production method characterized in that an asymmetric reaction is carried out using the asymmetric organic molecular catalyst of the second aspect to solve the above problems. It is.

  In this embodiment, the asymmetric reaction is preferably an asymmetric Diels-Alder reaction, and the optically active compound produced in the asymmetric Diels-Alder reaction is an isoquinuclidine derivative, which is represented by the following formula (2). The 1,2-dihydropyridine derivative is preferably a conjugated diene and the acrolein derivative represented by the following formula (3) is a dienophile.

（式（２）及び式（３）において、Ｒ^６〜Ｒ^１０、Ｒ^１２〜Ｒ^１４は水素原子又は一価の置換基を表わし、Ｒ^１１はアルキル基又はアリール基を表わす。）

(In Formula (2) and Formula (3), R ^{6 to} R ¹⁰ , R ^{12 to} R ¹⁴ represent a hydrogen atom or a monovalent substituent, and R ¹¹ represents an alkyl group or an aryl group.)

  The amino alcohol derivative salt of the present invention is excellent as a catalyst for an asymmetric reaction. By using this, the target optically active compound can be obtained with high chemical yield and high optical yield. In addition, the asymmetric organic molecular catalyst of the present invention has a relatively simple structure as compared with the asymmetric organic molecular catalysts found so far, and is easy to produce, and therefore uses an expensive metal. This is very advantageous not only for conventional organometallic catalysts but also for conventional asymmetric organic molecular catalysts in terms of production efficiency and cost.

  The asymmetric organic molecular catalyst of the present invention is particularly suitable as an asymmetric organic molecular catalyst for synthesizing optically active isoquinuclidine derivatives by asymmetric Diels-Alder reaction, and is selected with high chemical yield and high optical yield. The target product can be obtained. Optically active isoquinuclidine derivatives and optically active polysubstituted piperidine derivatives that are ring-opening products thereof are important synthetic intermediates for pharmaceuticals and physiologically active substances such as oseltamivir, vinblastine, reserpine, alcarides, Therefore, it is very useful for obtaining various pharmaceuticals and physiologically active substances at low cost and high efficiency.

  The asymmetric organic molecular catalyst of the present invention is an amino alcohol derivative salt represented by the following formula (1).

In Formula (1), R ¹ is an alkyl group or an aryl group, and the alkyl group is preferably one having 1 to 13 carbon atoms, and may be linear or branched, or may be cyclic. Moreover, the carbon atom on the alkyl group may be further substituted with another substituent such as an aryl group. Examples of the linear alkyl group include a methyl group, an ethyl group, and a propyl group. Examples of the branched alkyl group include isopropyl group, tert-butyl group, and sec-butyl group. As the cycloalkyl group, those having 3 to 8 carbon atoms which may have a branched structure are preferable, and examples thereof include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a 2-methylcyclopropyl group, and an adamantyl group. it can. Examples of the alkyl group substituted with an aryl group include a benzyl group. Examples of the aryl group include a phenyl group, a naphthyl group, a tolyl group, a xylyl group, and an ethylphenyl group. The carbon atom on the aryl group may further have an arbitrary substituent. In Formula (1), R ¹ is preferably an alkyl group or a substituted or unsubstituted phenyl group, and may be substituted with a linear or branched alkyl group having 1 to 7 carbon atoms or an alkyl group. It is more preferably a benzyl group or a phenyl group which may be substituted with an alkyl group, more preferably a benzyl group or a branched alkyl group having 1 to 5 carbon atoms, and an isopropyl group or a tert-butyl group. It is particularly preferred.

In Formula (1), R ² and R ³ are each independently a hydrogen atom or an aryl group. Examples of the aryl group are the same as those for R ¹ . In the formula (1), as R ² and R ^3, preferably R ² and R ³ are the same substituents together Exemplary substituents, which are substituted or unsubstituted phenyl group Are preferably a phenyl group substituted with a substituent having 5 or less carbon atoms or an unsubstituted phenyl group, and particularly preferably a phenyl group.

In Formula (1), R ⁴ is a hydrogen atom or a monovalent substituent, and examples of the monovalent substituent include an alkyl group, an aryl group, an acyl group, a silyl group, a sulfonyl group, and an alkoxycarbonyl group. Examples of the alkyl group and aryl group are the same as those for R ¹ . Examples of the acyl group include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a pivaloyl group, and a benzoyl group. Examples of the silyl group include trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, dimethylhexylsilyl group, tert-butyldimethylsilyl group, methyldiisopropylsilyl group, isopropyldimethylsilyl group, tert-butylmethoxyphenylsilyl group, tert- Examples include butoxydiphenylsilyl group, triphenylsilyl group, tert-butyldiphenylsilyl group, dimethylcumenylsilyl group, and tribenzylsilyl group. Examples of the sulfonyl group include a methanesulfonyl group, a trifluoromethanesulfonyl group, a benzenesulfonyl group, and a p-toluenesulfonyl group. Examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, and a tert-butoxycarbonyl group. In the formula (1), R ⁴ is preferably a hydrogen atom or a substituent commonly used as a hydroxyl-protecting group in the field of organic synthesis, and particularly preferably a hydrogen atom.

In Formula (1), R ⁵ is a hydrogen atom or an alkyl group, and the same alkyl group as R ¹ can be exemplified. In formula (1), R ⁵ is preferably an alkyl group having 5 or less carbon atoms or a hydrogen atom, and particularly preferably a hydrogen atom.

  In the formula (1), X is an organic acid that forms a salt with the amino alcohol derivative skeleton, and examples of the organic acid include picric acid, aliphatic and aromatic sulfonic acid, aliphatic and aromatic carboxylic acid, and the like. . Of these, aliphatic monocarboxylic acids and halogen-substituted products thereof are preferable, and specific examples include acetic acid, butyric acid, monofluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, monochloroacetic acid, dichloroacetic acid, and trichloroacetic acid. Of these, a halogen-substituted product of an aliphatic monocarboxylic acid is preferable, and trifluoroacetic acid is particularly preferable.

  Although the compound example of the amino alcohol derivative salt and asymmetric organic molecular catalyst of this invention represented by Formula (1) below is shown, this invention is not limited to these.

The amino alcohol derivative salt represented by the formula (1) can be synthesized by a known method. For example, when R ² and R ³ are aryl groups and the same substituents, as shown in the following scheme, an amino acid ester salt represented by the following formula (Y) is used as a starting material, and this and a Grignard reagent are mixed in a solvent such as ether. Then, if necessary, the hydroxyl group or amino group can be modified by a known method and further reacted with an organic acid.

  The amount of Grignard reagent used is usually about 3 to 4 mol per 1 mol of the amino acid ester salt of the raw material, and the amount of organic acid used when forming a salt with an organic acid is usually 1 mol of the amino alcohol derivative. About equimolar. The amino alcohol derivative salt represented by the formula (1) can be isolated and purified by chromatography, recrystallization and the like.

  Examples of the asymmetric synthesis reaction in which the asymmetric organic molecular catalyst of the present invention is used include Diels-Alder reaction, aldol reaction, Michael addition reaction and the like. The catalyst of the present invention is particularly useful as an asymmetric organic molecular catalyst in an asymmetric Diels-Alder reaction from the viewpoint of optical yield.

  The diene used as a raw material for the asymmetric Diels-Alder reaction is not particularly limited, but maximizes the effects of the asymmetric organic molecular catalyst of the present invention, that is, high endo / exo selectivity and enantioselectivity. Therefore, it is preferable to use a cyclic diene such as cyclopentadiene, cyclohexadiene or dihydropyridine as a raw material. Also, the dienophile is not particularly limited, and dienophiles that can be used for ordinary Diels-Alder reactions such as acrolein, methacrolein, and cinnamic aldehyde can be used.

  Although the usage-amount of the asymmetric organic molecular catalyst of this invention in an asymmetric Diels-Alder reaction is not specifically limited, 5-20 mol% is preferable with respect to the dienophile of a raw material normally, and 5-10 mol% is more preferable. If it is less than 5 mol% with respect to dienophile, the chemical yield and enantioselectivity of the Diels-Alder reaction may be lowered, which is not preferable. On the other hand, if it exceeds 20 mol%, there is no difference in effect, and from an economical viewpoint. It is not preferable.

  As a reaction solvent in the asymmetric Diels-Alder reaction, a nitrile solvent is preferably used. Examples of the nitrile solvent include acetonitrile and propionitrile. Moreover, it is also preferable that about 5% by volume of water is present in the solvent with respect to the solvent. Moreover, reaction temperature is not specifically limited, Usually, it is performed in the range of about 0-25 degreeC. From the viewpoint of enantioselectivity, 0 to 10 ° C is preferable.

  The asymmetric Diels-Alder reaction using the asymmetric organic molecular catalyst of the present invention is particularly a 1,2-dihydropyridine derivative (diene) represented by the following formula (2) and an acrolein derivative (dienophile) represented by the following formula (3). Is used for the synthesis of an isoquinuclidine derivative represented by the following formula (4), and the target optical isomer can be synthesized with a very high chemical yield and optical yield. Moreover, the isoquinuclidine derivative represented by the formula (4) can be easily converted into a polysubstituted piperidine derivative represented by the following formula (5) by ring opening.

In Formula (2), Formula (3), Formula (4), and Formula (5), R ^{6 to} R ¹⁰ and R ^{12 to} R ¹⁴ are each a hydrogen atom or a monovalent substituent, and R ¹¹ is an alkyl group. Or there is an aryl group. Examples of monovalent substituents represented by R ^{6 to} R ¹⁰ and R ^{12 to} R ¹⁴ include linear or branched alkyl groups, aryl groups, halogen atoms, hydroxyl groups, carboxyl groups, alkoxycarbonyl groups, acyl groups, and acyloxy groups. Group, an alkoxy group, an aryloxy group, and the like, and each substituent may be further substituted with another substituent. Examples of the alkyl group or aryl group of R ¹¹ include the same substituents as R ¹ in the above formula (1).

In Formula (2), Formula (3), Formula (4), and Formula (5), R ^{6 to} R ¹⁰ are preferably a hydrogen atom, and R ¹¹ is preferably a benzyl group or a phenyl group. Moreover, as R < ¹² > -R < ¹⁴ >, an alkyl group, an aryl group, a halogen atom, an acyl group, an acyloxy group, an alkoxy group, an aryloxy group etc. are preferable.

  The optically active isoquinuclidine derivative (4) synthesized by the asymmetric Diels-Alder reaction is a substance that becomes a precursor of oseltamivir, casarantine, reservin, vinblastine and the like. Moreover, the polysubstituted piperidine derivative represented by the above formula (5) obtained by ring-opening an optically active isoquinuclidine derivative is a precursor of aza sugar, piperidine alkaloid, and quinolidine alkaloid sugar. The present invention capable of synthesizing these compounds with a high chemical yield and a high optical yield is very useful for obtaining various pharmaceuticals and physiologically active substances at low cost and high efficiency.

(Synthesis of amino alcohol salts (1-A) to (1-F))
Amino alcohol salts (1-A) to (1-F) were synthesized by the scheme shown below.

In a 200 mL eggplant-shaped flask, 2.1 mmol of amino acid methyl esters (a) to (d) are taken and dissolved in 13 mL of diethyl ether. , 10 mmol) was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred for 12 hours while gradually returning to room temperature, and saturated NH ₄ Cl was added dropwise under ice cooling to stop the reaction. The reaction solution was extracted three times with ether, the organic layer was washed with a saturated aqueous NaCl solution and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized (Et ₂ O) to obtain white crystalline diphenylamino alcohols (iA) to (iF) in a yield of 70 to 80%. [(I-A): 72%, (i-B): 75%, (i-C): 73%, (i-D): 79%, (i-E): 71%, (i-F ): 78%]
12 mmol of (i-A) to (i-F) was taken in a 10 mL eggplant-shaped flask, dissolved in 2 mL of dichloromethane, and 0.12 mmol of trifluoroacetic acid was added under ice cooling. After stirring for 10 minutes, the reaction solution was distilled off under reduced pressure to quantitatively obtain amino alcohol trifluoroacetate salts (1-A) to (1-F).

¹ H-NMR data of the obtained amino alcohol salts (1-A) to (1-F) are shown below.
(1-A); ¹ H-NMR (400 MHz, CDCl ₃ , δ (ppm)): 0.95 (s, 9H), 4.25 (s, 1H) 7.12-7.17 (m, 2H) ), 7.23-7.31 (m, 4H), 7.59-7.61 (m, 4H)
(1-B); ¹ H-NMR (400 MHz, CDCl ₃ + CF ₃ CO ₂ D, δ (ppm)): 0.97 (d, 3H), 1.07 (d, 3H), 2.17-2 .22 (m, 1H), 4.27 (s, 1H), 7.32-7.45 (m, 10H)
(1-C); ¹ H-NMR (400 MHz, CDCl ₃ + CF ₃ CO ₂ D, δ (ppm)): 1.40 (d, 3H), 4.57-4.59 (m, 1H), 7 .32-7.47 (m, 10H)
(1-D); ¹ H-NMR (400 MHz, CDCl ₃ , δ (ppm)): 2.82-2.93 (m, 2H), 4.48-4.51 (m, 1H), 7. 08-7.36 (m, 11H), 7.53-7.57 (m, 4H)
(1-E); ¹ H-NMR (400 MHz, CDCl ₃ , δ (ppm)): 0.86 (s, 9H), 2.25 (brs, 6H), 4.16 (s, 1H), 6 .99 (d, 2H), 7.04 (d, 2H), 7.40-7.44 (m, 4H)
(1-F); ¹ H-NMR (400 MHz, CDCl ₃ , δ (ppm)): 0.94 (s, 9H), 4.14 (s, 1H), 6.94-7.03 (m, 4H), 7.49-7.52 (m, 4H)

(Synthesis of isoquinuclidine derivatives using amino alcohol salts (1-A) to (1-F) as catalysts)
In the scheme shown below, isoquinuclidine derivatives were synthesized using respective catalysts.

  0.01 mmol of catalysts (1-A) to (1-F) were taken in a 10 mL eggplant-shaped flask and dissolved in 0.5 mL of an acetonitrile / water mixed solvent (acetonitrile: water = 19: 1). Under ice-cooling at −25 ° C., 0.01 mmol of distilled acrolein (3) and 0.2 mmol of 1,2-dihydropyridine (2a) or (2b) were added and stirred at 0 ° C. for 24 hours. After completion of the reaction, water was added to the reaction solution and extracted with ether. The organic layer was washed with saturated NaCl aqueous solution and water, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain isoquinuclidine derivative (4a) or (4b). The obtained crude product was used for the next reaction without purification.

The isoquinuclidine derivative (4a) or (4b) obtained in the previous reaction was taken in a 10 mL eggplant-shaped flask, dissolved in 2 mL of ethanol, 0.05 mmol of sodium borohydride was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was distilled under reduced pressure, the resulting crude product was purified by column chromatography _(SiO 2, n-hexane: ethyl acetate = 1: 1) by separation and purification, quantify isoquinuclidine derivatives (5a) or (5b) Obtained.

  The optical yield of the isoquinuclidine derivative at the time of the above synthesis using each catalyst is HPLC data of the alcohol form (5a) or (5b) (Chiral Pack AS-H, n-hexane: 2-propanol manufactured by Daicel Chemical Industries, Ltd.) 93: 7). It shows in Table 1 about a chemical yield, an optical yield, etc.

  When any of the catalysts was used, high endo / exo selectivity was exhibited. In particular, in the catalysts (1-A) and (1-B), only the endo form could be selectively obtained. Furthermore, the enantioselectivity was also good, and in the catalysts (1-A) and (1-B), (7S) -endo bodies could be obtained with very excellent and high optical yield. The chemical yield was slightly lower for (1-E), but good results were obtained for the others.

  While the present invention has been described in connection with embodiments that are presently the most practical and preferred, the present invention is not limited to the embodiments disclosed herein. The amino alcohol derivative salt, the asymmetric organic molecular catalyst, and the asymmetric organic compound can be appropriately changed without departing from the spirit or idea of the invention that can be read from the claims and the entire specification. A method for producing an optically active compound using a molecular catalyst should also be understood as being included in the technical scope of the present invention.

  The asymmetric organic molecular catalyst of the present invention which is an amino alcohol derivative salt is a very excellent catalyst in terms of performance and cost. In particular, by using it as a catalyst for the asymmetric Diels-Alder reaction, optically active substances such as isoquinuclidine derivatives that are intermediates for pharmaceuticals and physiologically active substances can be obtained with high chemical yield and high optical yield. Therefore, the asymmetric organic molecular catalyst of the present invention is useful for efficient synthesis of pharmaceuticals and physiologically active substances.

Claims (5)

An amino alcohol derivative salt represented by the following formula (1).

(In Formula (1), R ¹ is an alkyl group or a substituted or unsubstituted phenyl group, R ² and R ³ are substituted or unsubstituted phenyl groups which are the same substituents, and R ⁴ is A hydrogen atom or a monovalent substituent, R ⁵ is a hydrogen atom or an alkyl group, and X represents an organic acid that forms a salt with the amino alcohol derivative skeleton in formula (1). An asymmetric organic molecular catalyst represented by the following formula (1).

(In Formula (1), R ¹ is an alkyl group or an aryl group, R ² and R ³ are each independently a hydrogen atom or an aryl group, R ⁴ is a hydrogen atom or a monovalent substituent, ⁵ is a hydrogen atom or an alkyl group, and X represents an organic acid that forms a salt with the amino alcohol derivative skeleton in formula (1). A method for producing an optically active compound, comprising performing an asymmetric reaction using the asymmetric organic molecular catalyst according to claim 2. The method for producing an optically active compound according to claim 3, wherein the asymmetric reaction is an asymmetric Diels-Alder reaction. The optically active compound is an isoquinuclidine derivative, the asymmetric Diels-Alder reaction is a 1,2-dihydropyridine derivative represented by the following formula (2) as a conjugated diene, and an acrolein derivative represented by the following formula (3) is a dienophile. The manufacturing method according to claim 4, wherein:

(In Formula (2) and Formula (3), R ^{5 to} R ⁹ and R ^{11 to} R ¹³ represent a hydrogen atom or a monovalent substituent, and R ¹⁰ represents an alkyl group or an aryl group.)