JPH09241269A - Immobilized silyl enol ether - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an immobilized silyl enol ether capable of synthesizing various organic compounds and facilitating the automation of a synthetic reaction due to simple and easy purification thereof by reaction with various carbon electrophilic reagents by bonding a silyl enol ether through a (thio)ether bond to an insoluble carrier. SOLUTION: This immobilized silyl enol ether has a structure of formula I [Q is an insoluble carrier such as a divinylbenzene-styrene copolymer or silica gel; Z is O, S or N; R<1> is an alkyl or an aryl; R<2> and R<3> are each H or an alkyl, an aryl, a halogen, a thioalkyl, a thioaryl, an alkoxy, an aryloxy or amino which may respectively have a substituent group]. The compound is obtained by reacting, e.g. the insoluble carrier having a structure of formula II having a benzyl halide with a compound of formula III (M is H or a metal; R is R<2> except H), providing a compound of formula IV and then reacting the resultant compound of formula IV with a silyl compound.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an immobilized silyl enol ether bound to an insoluble carrier via an ether or thioether bond, a method for producing the same, and a method for synthesizing an organic compound using the immobilized silyl enol ether, and more particularly, The present invention relates to a method for producing an organic compound library.

[0002]

2. Description of the Related Art In recent years, in the development of pharmaceuticals and the like, the molecular design of new compounds is carried out by chemically modifying or developing the molecules of compounds having a group of typical structures called lead compounds. However, as a search method for the lead compound, HTS (High Throughput Screening), which screens all compounds having a specific structure or composition in a bomb-like manner, has been attempted. Therefore, it is required to develop a method for supplying a large amount of sample to be applied to HTS as a compound library.

In order to construct a compound library, it is essential to automate the compound synthesizing operation and robotize it. Therefore, a polymer-supported reagent or a high-molecular-weight reagent for the purpose of simplifying the post-treatment operation and applying it to the flow system is required. Molecular catalysts and solid-phase synthesis methods using them are being developed. Solid phase synthesis methods using such polymers include solid phase synthesis of peptides and nucleic acids.

On the other hand, β-amino acids and β-amino acid amides derived therefrom, β-lactams, γ-aminoalcohols which are reductants and the like are compounded into pharmaceuticals and agricultural chemicals
And as intermediates between them. Many liquid phase synthesis methods of these compounds are known, but there is no example of solid phase synthesis method, and an efficient method for constructing a compound library thereof is not known.

Conventionally, silyl enol ethers have been used in many useful synthetic reactions such as aldol reactions (Weber, WP, Silicon Reagents for Org.
anicSynthesis, Springer-Verlag, Berlin, 1983
Year; Colvin, E .; W. Written by Silicon in Organic S
ynthesis, Butterworths, London, 1981, etc.),
Among them, β-by reacting a silyl enol ether compound and an imine in the presence of a Lewis acid,
Synthesis of aminocarbonyl compounds (Kleinman,
E. FIG. F. By Comprehensive Organic Synthesis, Tr
ost, B.I. M. Edited by Pergamon Press, New York, 19
1991, etc.) is also included. However, heretofore, synthesis examples of immobilized silyl enol ethers, and β-amino acids, β-amino acid amides, β-lactams using the same,
No examples have been reported of synthesizing γ-aminoalcohols that are reductants and further constructing a compound library thereof.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide an immobilized silyl enol ether useful for the synthesis of organic compounds and a method for producing the same. Another object of the present invention is to provide a method for synthesizing an organic compound using the immobilized silyl enol ether and a method for producing an organic compound library.

[0007]

As a result of intensive studies, the present inventor succeeded in solving the problem by the following constitution.

That is, the present invention relates to an immobilized silyl enol ether having a structure represented by the following general formula (I).

[0009]

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[In the formula (I), Q represents an insoluble carrier, and Z
Represents an oxygen atom, a nitrogen atom or a sulfur atom. R ¹ represents an alkyl group or an aryl group. R ² and R ³ are each hydrogen, an alkyl group which may have a substituent, an aryl group, a halogen atom, a thioalkyl group, a thioaryl group,
It represents a group selected from the group consisting of an alkoxy group, an aryloxy group, and an amino group, which may be the same or different from each other. ]

The present invention also provides an insoluble carrier having a halogenated benzyl group represented by the following general formula (II), a carboxylic acid, a carboxylic acid amide or a thiocarboxylic acid represented by the following general formula (III), or their An immobilized ester represented by the following general formula (IV) by reacting with a salt of
The present invention relates to a method for producing an immobilized silyl enol ether, comprising: a step of synthesizing an amide or thioester compound; and a step of reacting the immobilized ester, amide or thioester compound or its derivative obtained in the step with a silyl compound.

[0012]

[Chemical 6]

[In the formula (II), Q represents an insoluble carrier,
X represents a halogen atom. ]

[0014]

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[In the formula (III), Z represents an oxygen atom, a nitrogen atom or a sulfur atom, and M represents a hydrogen atom or a metal atom. R represents a group selected from the group consisting of an alkyl group which may have a substituent, an aryl group, a halogen atom, a thioalkyl group, a thioaryl group, an alkoxy group, an aryloxy group and an amino group. ]

[0016]

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[In the formula (IV), Q and R are respectively represented by the formula (I
It has the same meaning as in (I) and (III). The present invention also provides a synthetic step of synthesizing an immobilized organic compound by reacting the immobilized silyl enol ether with a carbon electrophile, and separating an insoluble carrier from the immobilized organic compound obtained in the step. And a carrier separation step of removing the organic compound to isolate the organic compound.

Further, the present invention provides a method for producing an organic compound library comprising a group of organic compounds having a structure common to each other, wherein the immobilized silyl enol ether is reacted with a carbon electrophile to obtain an immobilized organic compound. It relates to a method comprising a step of synthesizing a compound group and a carrier separation step of separating and removing an insoluble carrier from the immobilized organic compound group obtained in the above step to isolate the organic compound group.

By reacting the immobilized silyl enol ether of the present invention with various carbon electrophiles, various organic compounds can be synthesized by a simple operation. Further, since the purification operation after the synthesis reaction is only washing of the insoluble carrier, robotization and automation of the synthesis reaction are easy,
Suitable for preparing organic compound libraries. Further, it can be recovered and reused after the reaction is completed. In particular, when an imine compound is used as a carbon electrophile, various γ-amino alcohol derivatives, β-lactam derivatives, carboxylic acid derivatives, acid amide derivatives, and other organic compounds or organic compound libraries consisting of these organic compound groups Can be provided, and its applicability is extremely wide.

[0020]

Embodiments of the present invention will be described below. (1) Immobilized Enol Ether of the Present Invention The immobilized enol ether of the present invention has the general formula (I) above.
It has a structure shown by. That is, it has a structure in which a silyl enol ether group is immobilized on an insoluble carrier through an ether bond or a thioether bond.

In the formula (I), Z represents an oxygen atom, a nitrogen atom or a sulfur atom. It is preferably a sulfur atom, and the silyl enol ether group is preferably fixed to the insoluble carrier through a thioether bond.

R ¹ represents an alkyl group or an aryl group. It is preferably a lower alkyl group having 1 to 10 carbon atoms or an aryl group, and specific examples thereof include a lower alkyl group such as a methyl group, an ethyl group, a propyl group and a butyl group, or an aryl group such as a phenyl group.

R ² and R ³ are each a hydrogen atom, an alkyl group which may have a substituent, an aryl group, a halogen atom, a thioalkyl group, a thioaryl group, an alkoxy group,
It represents a group selected from the group consisting of an aryloxy group and an amino group, and may be the same or different from each other. The alkyl group is preferably a linear or branched alkyl group having 1 to 10 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, a propyl group and a butyl group. A phenyl group is mentioned as an aryl group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. S-methyl group as the thioalkyl group,
S-ethyl group, S-propyl group, S-butyl group, S-pentyl group, S-isopropyl group, S-isobutyl group, S
-Tertiary butyl group and the like. As the thioaryl group, S-phenyl group, S-pyridyl group, S-α
Examples include -naphthyl group and S-β-naphthyl group. Examples of the alkoxy group include a methoxy group and an ethoxy group. A benzyloxy group is mentioned as an aryloxy group. In addition, each group may have a hydrogen atom substituted with an arbitrary substituent.

Q represents an insoluble carrier and is not particularly limited as long as it can bind to and immobilize a compound molecule and may be an organic polymer compound or an inorganic substance. Examples of the organic polymer compound include those selected from the group consisting of vinyl polymers such as divinylbenzene-styrene copolymers, polyacrylamide resins and polyethylene resins, and polymer compounds such as polyamide resins. Examples of the inorganic substance include porous inorganic compounds such as silica gel and alumina, and preferably selected from the group consisting of silica gel and alumina.

Preferred examples of the immobilized silyl enol ether of the present invention include compounds having the following structures.

[0026]

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[In the formula, Me represents a methyl group and Ph represents a phenyl group. ]

(2) Method for producing immobilized enol ether of the present invention The immobilized enol ether of the present invention has the general formula (I)
The insoluble carrier having a halogenated benzyl group represented by I) is reacted with the carboxylic acid, carboxylic acid amide or thiocarboxylic acid represented by the general formula (III) or a salt thereof to react with the general formula (IV). Manufactured by a method comprising a step of synthesizing an immobilized ester, amide or thioester compound represented by: and a step of reacting the immobilized ester, amide or thioester compound or its derivative obtained in the above step with a silyl compound. .

First, the insoluble carrier represented by the general formula (II) will be described. In the formula (II), Q represents an insoluble carrier and X represents a halogen atom. That is,
There is no particular limitation as long as it has a halogenated benzyl group in the molecule, and it may be either an organic polymer compound or an inorganic substance. For example, it can be appropriately selected and used from catalyst carriers, carriers used in organic synthesis such as peptide synthesis, and the like. Preferred examples of the organic polymer compound include a divinylbenzene-styrene copolymer having a side chain containing a halogenated benzyl group, a polyacrylamide resin, a vinyl polymer such as a polyethylene resin, and a polyamide resin. Examples of the inorganic substance include silica gel, alumina, and the like, which have an organic group containing a halogenated benzyl group on the surface or the like. Moreover, the position of the halogenated methyl group in the halogenated benzyl group may be any of the o-position, m-position and p-position. Specifically, it is effective to use a matrix composed of divinylbenzene-styrene copolymerization, silica gel, alumina, or the like, to which a handle portion such as a benzyl group is bonded via a spacer portion such as polyoxyethylene or polydimethylacrylamide. Such an insoluble carrier can be appropriately selected from carriers and the like currently used for peptide synthesis. Below (Chemical 10)
An example of the structure of the spacer portion and the handle portion is shown in FIG.

[0030]

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The carboxylic acid, carboxylic acid amide, thiocarboxylic acid or salt thereof represented by the general formula (III) will be described below.
In the above, Z represents an oxygen atom, a nitrogen atom or a sulfur atom, and preferably a sulfur atom. In addition, M represents a hydrogen atom or a metal atom. R represents a group selected from the group consisting of an alkyl group which may have a substituent, an aryl group, a halogen atom, a thioalkyl group, a thioaryl group, an alkoxy group, an aryloxy group and an amino group. The alkyl group is preferably a linear or branched alkyl group having 1 to 10 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, a propyl group and a butyl group. Moreover, a phenyl group is mentioned as an aryl group. Examples of the halogen atom include a chlorine atom and a bromine atom. Examples of the alkoxy group include a methoxy group and an ethoxy group. A benzyloxy group etc. are mentioned as an aryloxy group.

Specific examples of such carboxylic acid, carboxylic acid amide or thiocarboxylic acid or salts thereof include thioacetic acid, thiopropionic acid, etc., or their sodium salts, potassium salts, cesium salts, etc.

In the method for producing an immobilized silyl enol ether of the present invention, such an insoluble carrier having a halogenated benzyl group is reacted with the carboxylic acid, carboxylic acid amide or thiocarboxylic acid or a salt thereof. The immobilized ester, amide or thioester compound represented by the general formula (IV) is synthesized. Here, in the formula (IV), Q and R have the same meanings as in formulas (II) and (III), respectively. This synthetic reaction is shown in the following reaction formula.

[0034]

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Thus, the ester group is added to the insoluble carrier,
An amide group or a thioester group is introduced. This synthetic reaction is carried out by reacting at around room temperature in an aprotic polar solvent such as dimethylformamide (DMF), acetamide, N-methylpyrrolidone, hexamethylphosphoric triamide and the like. Introduction of an ester group, an amide group or a thioester group is carried out by IR spectrum 1693c.
It can be confirmed by absorption due to stretching vibration of m ^-1
The introduction rate can be determined by appropriately determining a halide such as chlorine.

In the present invention, the immobilized silyl enol ether is produced by reacting the thus-obtained immobilized ester, amide or thioester compound with a silyl compound. Examples of the silyl compound used here include trimethylsilyl trifluoromethanesulfonate (hereinafter abbreviated as "TMSOTf") and the like.

Specifically, the immobilized ester, amide or thioester compound is treated with trimethylsilyltrifluoromethanesulfonate (TMSOT) in the presence of a tertiary amine such as triethylamine in a solvent such as methylene chloride.
The corresponding immobilized silyl enol ether can be obtained by treating with a silyl compound such as f).

Alternatively, it can also be obtained by converting the immobilized ester, amide or thioester compound into a derivative of the desired immobilized ester, amide or thioester compound in advance and then reacting with a silyl compound such as trimethylsilane chloride. You can For example, a method may be mentioned in which lithium diisopropylamide (LDA) or the like is allowed to act on an immobilized ester, amide, or thioester compound, and the generated lithium enolate is captured by trimethylsilane chloride or the like.

The immobilized silyl enol ether thus obtained is stable and can be stored. (3) Method for synthesizing organic compound of the present invention The synthesis of the organic compound of the present invention is carried out by reacting the above-mentioned immobilized silyl enol ether of the present invention with a carbon electrophile to synthesize an immobilized organic compound. When,
A separation step of separating and removing the insoluble carrier from the immobilized organic compound obtained in the above step is performed.

The immobilized silyl enol ethers of this invention react with various carbon electrophiles to give immobilized organic compounds containing ester, amide or thioester groups. That is, an ester group, an amide group, or a thioester group is formed by the reaction of a silyl enol ether group and a carbon electrophile, and an adduct in which an organic compound and an insoluble carrier are bonded via these groups is obtained. Here, as the carbon electrophile, carbonyl compounds such as aldehydes and ketones or imine compounds derived from them,
Examples thereof include secondary or tertiary halogenated alkyl compounds, which can be appropriately selected according to the structure of the desired organic compound. The carbonyl compound is not particularly limited and almost any carbonyl compound can be used, and specific examples thereof include acetaldehyde, benzaldehyde and acetophenone. Further, examples of the imine compound include benzylideneaniline. Further, the same reaction can be carried out by using an aldehyde and an amine which generate an imine in the catalytic reaction system instead of the imine compound. Examples of such a combination of aldehyde and amine include benzaldehyde and aniline.

The immobilized silyl enol ether of the present invention reacts particularly smoothly with an imine compound to give a desired immobilized organic compound in good yield. When an imine compound is used as the carbon electrophile, the obtained immobilized organic compound is an immobilized β-aminoester compound having a β-aminoester structure or an immobilized β-aminothioester compound. In the method of the present invention, an immobilized β-aminothioester compound is preferably prepared by using an imine compound and an immobilized silyl enol ether in which Z in the general formula (I) is a sulfur atom derived from the immobilized thioester compound. It is particularly effectively applied when synthesizing. The reaction formula below shows a reaction for synthesizing an immobilized β-aminothioester compound by reacting the immobilized silyl enol ether of the present invention with an imine compound.

[0042]

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[In the formula, R ⁴ and R ⁵ each represent an organic group. ] The reaction between the immobilized silyl enol ether of the present invention and the carbon electrophile is preferably carried out in the presence of a Lewis acid. As the Lewis acid catalyst, a general Lewis acid can also be used, but among them, a metal salt of trifluoromethanesulfonic acid is preferable, and in particular, scandium trifluoromethanesulfonate [Sc (CF ₃ SO ₃ ) ₃ :
Abbreviated as “Sc (OTf) _3. ” Here, OTf represents trifluoromethanesulfonic acid. The same applies hereinafter. ] Or hafnium trifluoromethanesulfonate [Hf (OT
f) ₄ ] is preferably used. When these trifluoromethanesulfonic acid metal salts are used, the amount is 1 to 10 with respect to the number of moles of the immobilized silyl enol ether used.
Use of a catalytic amount of 0 mol%, preferably 5 to 20 mol% gives the desired immobilized organic compound in good yield. A halogenated hydrocarbon such as methylene chloride or chloroform is preferably used as a reaction solvent in this synthesis reaction. The reaction temperature is 0 to 80 ° C, preferably 10 to 30 ° C.
The reaction time varies slightly depending on the kind of the starting material compound as a substrate and the like, and is about 1 hour to 48 hours, but about 20 hours is usually sufficient. After the reaction, the Lewis acid catalyst and unreacted reagents can be removed by a simple operation such as centrifugation or filtration.

In the present invention, the insoluble carrier is then separated and removed from the immobilized organic compound obtained in the above synthesis step to isolate the desired organic compound. The insoluble carrier is bound to the organic compound via an ester group, an amide group or a thioester group. Therefore, as a method for separating the insoluble carrier and the desired organic compound, a method of cleaving this bond is particularly preferable. Not limited. Specifically, the corresponding alcohol, aldehyde, carboxylic acid, acid amide, ester, or thioester can be easily obtained by subjecting to a reaction such as reduction, saponification, aminolysis, transesterification, etc. by a conventional method. That is, in the case of reduction, the immobilized organic compound is treated with a metal hydride complex compound such as lithium borohydride in a solvent such as ether or tetrahydrofuran to give a corresponding alcohol, and in the presence of palladium activated carbon. Treatment with triethylsilane at 30 gives the aldehyde. In the case of saponification, the immobilized organic compound is treated with an alkali compound such as sodium hydroxide to give a carboxylic acid. In the case of aminolysis, the immobilized organic compound is treated with ammonia or an organic solvent containing a primary or secondary amine to give an acid amide. In the case of transesterification,
The immobilized organic compound is treated with alcohol or thiol to give an ester form. After the reaction, these reaction products can be isolated from the reaction system by a simple operation such as filtration or precipitation, and extraction or precipitation.

In the synthetic method of the present invention, when an immobilized β-aminoester compound or an immobilized β-aminothioester compound is synthesized by using an imine compound as a carbon electrophile, it can be synthesized by the above-mentioned methods such as reduction. , Corresponding γ-amino alcohol, β-amino aldehyde, β-
It can be converted into amino acids, β-amino acid amides, β-amino acid esters and the like. Further, when treated with an acid such as a protonic acid or a Lewis acid, or a base such as lithium isopropylamide or phenylmagnesium bromide, an intramolecular cyclization reaction occurs, and a β-lactam derivative useful as a drug can be obtained.

The insoluble carrier separated and removed has an alcohol (-OH) or thiol (-SH) structure at the terminal,
It is possible to reuse the compound as an immobilized ester, amide or thioester compound by recovering and performing a simple operation such as washing and then acylating it by a conventional method. (4) Method for producing organic compound library of the present invention In the method for producing organic compound library of the present invention, a group of immobilized organic compounds obtained by reacting the immobilized silyl enol ether with the carbon electrophile according to claim 1. And a carrier separation step of separating and removing the insoluble carrier from the immobilized organic compound group obtained in the above step to isolate the organic compound group.

An organic compound library consisting of a plurality of organic compound groups having a common structure is used as a method for searching lead compounds in the development of new drugs.
It can be used to supply large quantities of analytes for TS. Normally, in HTS, a robot that performs micro-synthesis and analysis in a fully automatic manner is used in order to carry out a huge amount of experiments at high speed and at low cost, but the immobilized silyl enol ether of the present invention can be stored. Since the purification operation after the synthesis reaction is simple, such as only washing the insoluble carrier,
It can be easily robotized and automated, and is suitable for preparing organic compound libraries.

Examples of the organic compound library which can be produced by the method of the present invention include γ-amino alcohol derivative groups, β-amino acid derivative groups, β-amino acid amide derivative groups, which are obtained by using imine compounds as carbon electrophiles. Examples include β-lactam derivatives. As starting materials used for synthesizing these organic compounds, the same raw materials as those described in the method for synthesizing organic compounds can be used. The reaction solvent, reaction conditions, and the like are the same as those in the method for synthesizing the organic compound.

As an automation method, the principle of peptide synthesis, which is currently being automated, can be used. That is, a mixture of immobilized silyl enol ether, Lewis acid catalyst and carbon electrophile is mixed with a solvent by shaking or ultrasonic irradiation in a reaction vessel equipped with a filter, and unreacted reagents are sucked after the reaction. Alternatively, it is filtered off under pressure. After washing the immobilized product, the reaction of cleaving the bond between the insoluble carrier and the organic compound is performed to separate the insoluble carrier and the organic compound, and then the insoluble carrier is separated by a simple operation such as filtration, extraction or precipitation. Can be removed to isolate the organic compound. A high quality compound library can be prepared by such a method.

[0050]

Embodiments of the present invention will be described below. In addition,
In the examples, various physical properties were measured by the following instruments and methods. (1) NMR spectrum: measured using Jeol JNM-GX270 FT-NMR (manufactured by JEOL Ltd.) (solvent is CDC
l ₃ ). (2) IR spectrum: Horiba FT-300 spectrometer
(Manufactured by Horiba Ltd.).

[0051]

Example 1 <Synthesis (1) of Immobilized Thioester Compound> Chloromethylated (styrene-1% -divinylbenzene copolymer) resin (10.0 g, chlorine content: 1.1) as an insoluble carrier.
5 mmol / g) was suspended in DMF (60 ml) and slowly stirred with potassium thioacetate (2.63 g) for 19 hours. The reaction mixture was filtered, the resin was washed with water, dioxane, and then with ether, and dried to obtain an S-acetylated resin (10.3 g) which was an immobilized thioester compound. This reaction is shown in the following reaction formula. The formation of the thioester bond was confirmed by stretching vibration at 1693 cm ^{-1 in} the IR spectrum, and the introduction rate was 95% by quantitative determination of residual chlorine.
Was calculated. FIG. 1 shows the IR spectrum of the S-acetylated resin.

[0052]

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[0053]

Example 2 <Synthesis (2) of Immobilized Thioester Compound> Instead of potassium thioacetate, potassium thiopropionate (2.0
The same reaction as in Example 1 was carried out using S.g) to give an S-propionylated resin (2.
1 g) was obtained. The introduction rate was 100%.

[0054]

Example 3 <Synthesis (3) of Immobilized Thioester Compound> In place of potassium thioacetate, potassium benzyloxyxyacetic acid thioate (2.0 g) was used to carry out the same reaction as in Example 1 for immobilization. S-benzyloxyacetylated resin (2.1 g), which is a thioester compound, was obtained. Introduction rate is 10
It was 0%.

[0055]

Example 4 <Synthesis (1) of Immobilized Silyl Enol Ether> The S-acetylated resin (5.0 g, acetyl group introduction amount: 1.05 mmol / g) obtained in Example 1 was dissolved in methylene chloride. Swell, triethylamine (1.91 g) and TMSO
Tf (3.5 g) was added, and the mixture was stirred at room temperature for 22 hours. The reaction mixture was filtered, and the resin was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, dioxane and ether and then dried to obtain the corresponding immobilized silyl enol ether (5.1).
g). This has the same general formula (I) as R ¹ = -CH ₃ ,
This corresponds to the case of R ² = R ³ = H. This reaction is shown in the following reaction formula. The IR spectrum of the product is shown in FIG.

[0056]

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[0057]

Example 5 <Synthesis (2) of Immobilized Silyl Enol Ether> The S-propionylated resin (5.0 g) obtained in Example 2 was used instead of the S-acetylated resin, and the same as in Example 4. Was carried out to obtain the corresponding immobilized silyl enol ether (5.1 g). This is represented by R ¹ in the general formula (I).
_{^{= R 3 = -CH 3, R}} 2 = H ^{or,, R 1 = R 2 =} -C
This corresponds to the case where H ₃ and R ³ = H.

[0058]

Example 6 <Synthesis (3) of Immobilized Silyl Enol Ether> S-A
Instead of the cetylated resin, the S-benzylo obtained in Example 3 was used.
Same as Example 4 using xyacetylated resin (5.0 g)
Such a reaction is performed and the corresponding immobilized silyl enol ether is
Ter was obtained (5.1 g). This is the general formula
(I) Medium, R ¹= -CH_Three, R^Two= H, R^Three= -OCH_TwoP
h or R¹= -CH_Three, R^Three= H, R^Two= -OCH_Two
This corresponds to the case of Ph (Ph represents a phenyl group).

[0059]

Example 7 <Reaction (1) of Immobilized Silyl Enol Ether with Imine> The immobilized silyl enol ether (234 mg, 0.2 mmol) obtained in Example 6 was swollen in methylene chloride (2 ml), and the mixture was allowed to stand at room temperature. Sc (OTf) ₃ (9.
8 mg, 10 mol%) and benzylidene aniline (36
mg, 0.24 mmol) was added. After stirring at room temperature for 20 hours, a saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the resin was washed successively with water, dioxane and ether. After drying, the corresponding immobilized β-aminothiocarboxylic acid derivative (244 mg) was obtained. This reaction is shown in the following reaction formula.

[0060]

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[0061]

Example 8 <Synthesis of γ-aminoalcohol> The immobilized β-aminothiocarboxylic acid derivative (243 g) obtained in Example 7 was suspended in ether (4 ml), and lithium borohydride (2
2 mg) was added and the mixture was stirred at room temperature for 12 hours. Phosphate buffer (pH = 7) and sodium hydroxide solution were added and filtered, and then the product was extracted from the aqueous phase with ether. The organic phase was dried over anhydrous sodium sulfate and then concentrated to obtain the corresponding γ-amino alcohol (45 mg, 67%). The product is T
LC gave a single spot. This reaction is shown in the following reaction formula. The ¹ H-NMR spectrum and the ¹³ C-NMR spectrum of the product are shown in FIG. 3 and FIG. 4, respectively. The separated simple substance had a thiol group at the terminal, and could be converted to an immobilized thiocarboxylic acid that was a raw material of the immobilized silyl enol ether by acylation in a conventional manner.

[0062]

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[0063]

INDUSTRIAL APPLICABILITY The immobilized silyl enol ether of the present invention can synthesize various organic compounds by a simple operation by reacting with various carbon electrophiles. Further, since the purification operation after the synthesis reaction is only washing of the insoluble carrier, robotization and automation of the synthesis reaction are easy,
Suitable for preparing organic compound libraries. Furthermore, it can be recovered and reused after the reaction.

[Brief description of drawings]

1 is an IR spectrum diagram of the immobilized thioester compound obtained in Example 1. FIG.

2 is an IR spectrum diagram of the immobilized silyl enol ether obtained in Example 4. FIG.

FIG. 3 shows the γ-amino alcohol obtained in Example 8.
^{It is a} < ¹ > H-NMR spectrum figure.

FIG. 4 shows the γ-amino alcohol obtained in Example 8.
It is a < ¹³ > C-NMR spectrum figure.

Claims (13)

[Claims] 1. An immobilized silyl enol ether having a structure represented by the following general formula (I). Embedded image [In the formula (I), Q represents an insoluble carrier, Z is an oxygen atom,
Represents a nitrogen atom or a sulfur atom. R ¹ represents an alkyl group or an aryl group. R ² and R ³ are each selected from the group consisting of a hydrogen atom, an optionally substituted alkyl group, an aryl group, a halogen atom, a thioalkyl group, a thioaryl group, an alkoxy group, an aryloxy group, and an amino group. Groups, which may be the same or different from each other. ] 2. The immobilized silyl enol ether according to claim 1, wherein Z in the formula (I) is a sulfur atom. 3. The insoluble carrier is divinylbenzene-
The organic polymer compound selected from the group consisting of a styrene copolymer, a polyacrylamide resin, a polyethylene resin, and a polyamide resin, or an inorganic substance selected from the group consisting of silica gel and alumina. Immobilized silyl enol ether as described. 4. An insoluble carrier having a halogenated benzyl group represented by the following general formula (II);
A step of reacting with a carboxylic acid or thiocarboxylic acid represented by I) or a salt thereof to synthesize an immobilized ester, amide or thioester compound represented by the following general formula (IV), and immobilization obtained in the above step The method for producing an immobilized silyl enol ether according to any one of claims 1 to 3, which comprises a step of reacting a modified ester, amide or thioester compound or a derivative thereof with a silyl compound. Embedded image [In the formula (II), Q represents an insoluble carrier and X represents a halogen atom. ] [In the formula (III), Z represents an oxygen atom, a nitrogen atom or a sulfur atom, and M represents a hydrogen atom or a metal atom. R represents a group selected from the group consisting of an alkyl group which may have a substituent, an aryl group, a halogen atom, a thioalkyl group, a thioaryl group, an alkoxy group, an aryloxy group and an amino group. ] [In the formula (IV), Q and R are respectively the formulas (II) and (I
It has the same meaning as in II). ] 5. The method for producing an immobilized silyl enol ether according to claim 4, wherein Z in the general formulas (III) and (IV) is a sulfur atom. 6. A synthetic step of synthesizing an immobilized organic compound by reacting an immobilized silyl enol ether according to claim 1 with a carbon electrophile.
A method for synthesizing an organic compound, which comprises a step of separating an insoluble carrier from the immobilized organic compound obtained in the above step to isolate the organic compound. 7. The insoluble carrier is separated and removed from the immobilized organic compound by subjecting the immobilized organic compound to a reduction reaction, a saponification reaction, an aminolysis reaction, or a transesterification reaction in the carrier separation step. The method for synthesizing an organic compound according to claim 6, wherein the organic compound is isolated. 8. The method for synthesizing an organic compound according to claim 6, wherein in the synthesis step, an imine compound is used as a carbon electrophile and an immobilized β-aminothioester is synthesized as an immobilized organic compound. . 9. The step of separating the carrier, wherein the immobilized β-aminothioester synthesized in the synthesizing step is reduced to separate and remove the insoluble carrier, and the γ-amino alcohol derivative is isolated. 8. The method for synthesizing the organic compound according to 8. 10. In the carrier separation step, the insoluble carrier is separated and removed by alkali-saponifying the immobilized β-aminothioester synthesized in the synthesis step, and the β-amino acid derivative is isolated. The method for synthesizing the organic compound according to claim 8. 11. In the carrier separation step, the insoluble carrier is separated and removed by reacting the immobilized β-aminothioester synthesized in the synthesis step with ammonia or amine, and the β-amino acid amide derivative is isolated. The method for synthesizing the organic compound according to claim 8. 12. In the carrier separation step, the insoluble carrier is separated and removed by treating the immobilized β-aminothioester synthesized in the synthesis step with an acid or a base to isolate the β-lactam derivative. The method for synthesizing an organic compound according to claim 8. 13. A method for producing an organic compound library comprising a group of organic compounds having a mutually common structure, wherein the immobilized silyl enol ether according to claim 1 and a carbon electrophile are used. Characterized by comprising a step of reacting to synthesize an immobilized organic compound group, and a carrier separation step of separating and removing an insoluble carrier from the immobilized organic compound group obtained in the step to isolate the organic compound group how to.