JP2000281661A - Optically active piperazine derivative, its polymer, and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject novel compound, useful as a monomer constituting a structural unit of high-molecular-weight asymmetric catalyst, which can be easily separated from the reaction products and reused, and exhibits notable effects in catalytic activity and asymmetric yield. SOLUTION: This compound is shown by formula I [R1 is H, a 1-6C alkyl or (substituted) 7-10C aralkyl; R2 is H, a 1-6C alkyl or shown by the formula RaRbRcSi (Ra, Rb and Rc are each a 1-6C alkyl, phenyl or the like); R3 and R4 are each H, cyano, a halogen, 1-6C alkyl or the like; X is carbonyl or sulfonyl; Ar is a (substituted) divalent aromatic group; and (s) is 0 or 1], e.g. 2-(t-butyldimethylsilyloxymethyl)-4-(4-vinyltosyl)piperazine. It can be obtained by reacting a sulfonyl halide shown by formula III (hal is a halogen) with an optically active piperazine derivative shown by formula IV, wherein the compound shown by formula III is obtained by reacting a halogenation agent with a compound shown by formula II [M is H, or an alkali or an alkaline-earth metal].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an optically active piperazine derivative useful in an asymmetric reduction reaction and to an asymmetric polymer catalyst obtained by polymerizing the compound.

[0002]

2. Description of the Related Art Hitherto, polymers obtained by polymerizing optically active monomers have been known. Such a polymer has various functions, and is expected to be put to practical use as a medium for optical resolution or an asymmetric synthesis catalyst, and intensive research is being conducted.
Above all, application studies on stereoselective organic reactions using synthetic chiral polymers as asymmetric catalysts have characteristics that differ from general solvent homogeneous reactions in that they use a unique reaction field constructed by polymers. In particular, this is an area in which progress has been remarkable.

In addition, polymer catalysts have many industrial advantages in that they are generally easier to separate from the reaction system than monomolecular catalysts and can be reused.

[0004] From such a viewpoint, for example, the following are known as polymerized asymmetric catalysts.

(A) Polymer. , 28 , 1005
-1008 (1987) discloses that a chiral monomer is prepared by reacting (S)-(-)-2-amino-3- (4-hydroxy) -1,1-diphenylpropan-1-ol with 4-vinylbenzyl chloride. And a polymer asymmetric catalyst (7) obtained by copolymerizing the polymer with styrene and divinylbenzene. Then, using this polymer asymmetric catalyst (7), acetophenone o-
Asymmetric reduction of methyl oxime has yielded optically active amines in high asymmetric yields (see formula below).

[0006]

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(B) Tetrahedron: Asym
metry. , 16 , 2687 (1995)
A polymer-supported catalyst (8) obtained by reacting (S) -α, α-diphenyl-2-pyrrolidenemethanol with poly-p-styreneboronic acid is described. Then, the asymmetric reduction of ketone such as acetophenone is performed using this product (see the following formula).

[0008]

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(C) Polymer. , 36 , 621
(1995) reports that a polymer represented by the following general formula (9) is useful as a catalyst for asymmetric reduction of ketones.

[0010]

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[0011]

[Problems to be solved by the invention]

However, although the polymer asymmetric catalysts described in the above (A) to (C) have excellent asymmetric selectivity,
Raw materials for synthesizing monomers are relatively expensive,
Synthesis is also complicated.

In addition, when the asymmetric catalyst is polymerized, the optical selectivity of the monomer is often not maintained, and the stereoselectivity is greatly improved by increasing the optically active monomer. Was few.

Accordingly, the present invention provides an asymmetric synthesis reaction catalyst, particularly an asymmetric reduction catalyst, which can be easily separated from a reaction product, can be reused, and has a catalytic activity and an asymmetric yield. It is an object of the present invention to provide an asymmetric polymer catalyst which can obtain an effect far superior to that of the monomer composed of the above and can be produced at low cost, a method for producing the same, and a raw material monomer for the asymmetric polymer catalyst.

[0015]

It is known that certain optically active piperazine derivatives are useful catalysts for various asymmetric reduction reactions (Japanese Patent Application No. 11-58,704).
However, this is a single-molecule catalyst, and has a problem in separation from a reaction product and reuse of the catalyst.

Therefore, the present inventors have synthesized a copolymer of this optically active piperazine derivative and another unsaturated monomer having a polymerizable double bond, and this asymmetric polymer is an asymmetric polymer. They have found that they are useful as catalysts, and have completed the present invention. That is, the present invention provides the following inventions (1) to (5). (1) General formula (1)

[0017]

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(Where R¹Is a hydrogen atom_,C_1-6Archi
Or an optionally substituted C _7-10Aralkyl group
And R^TwoIs a hydrogen atom, C_1-6Alkyl group or Ra
Rb Rc represents a Si group, wherein Ra, Rb and Rc are the same or
Differently, C_1-6Alkyl group, C_3-8Cycloalkyl
Represents a phenyl group or a phenyl group. R^Three, R^FourAre independent
Hydrogen atom, cyano group, halogen atom, C_1-6Archi
Group or C_1-6X represents an alkoxycarbonyl group, and X is
Represents a carbonyl group or a sulfonyl group, and Ar is a substituent
Represents a divalent aromatic group which may have
Represents 1. ), An asymmetric carbon on the piperazine ring
Optically active piperazine derivative having an atom. (2) General formula (2)

[0019]

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Where R¹Is a hydrogen atom_,C_1-6Archi
Or an optionally substituted C _7-10Aralkyl group
And R^TwoIs a hydrogen atom, C_1-6Alkyl group or Ra
Rb Rc represents a Si group, wherein Ra, Rb and Rc are the same or
Differently, C_1-6Alkyl group, C_3-8Cycloalkyl
Represents a phenyl group or a phenyl group. R^Three, R^FourAre independent
Hydrogen atom, cyano group, halogen atom, C_1-6Archi
Group or C_1-6X represents an alkoxycarbonyl group, and X is
Represents a carbonyl group or a sulfonyl group, and Ar is a substituent
Represents a divalent aromatic group which may have
Represents 1 and n represents an integer of 1 to 1000. )
Oligomer or poly having the structural unit of the compound
Ma.

(3) The following general formulas (2), (3) and (4)

[0022]

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Where R¹Is a hydrogen atom_,C_1-6Archi
Or an optionally substituted C _7-10Aralkyl group
And R^TwoIs a hydrogen atom, C_1-6Alkyl group or Ra
Rb Rc represents a Si group, wherein Ra, Rb and Rc are the same or
Differently, C_1-6Alkyl group, C_3-8Cycloalkyl
Represents a phenyl group or a phenyl group. R^Three, R^FourAre independent
Hydrogen atom, cyano group, halogen atom, C_1-6Archi
Group or C_1-6Represents an alkoxycarbonyl group;⁶,
R⁷, R⁸, R⁹, R^TenAnd R¹¹Are independent
And a hydrogen atom or C_1-6Represents an alkyl group;^FiveIs the water
Elementary atom, C_1-6Alkyl group, C_1-6Alkoxy group or ha
X represents a carbonyl group or a sulfonyl
And Ar represents a divalent group which may have a substituent.
Represents an aromatic group, s represents 0 or 1, and n represents 1 to 10.
Represents an integer of 00, and m and l are each independently 0 or
Represents an integer of 1 to 1000, and m and l are simultaneously 0
is not. ) Having a structural unit of the compound represented by
Rimmer. (4) General formula (1)

[0024]

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Where R¹Is a hydrogen atom_,C_1-6Archi
Or an optionally substituted C _7-10Aralkyl group
And R^TwoIs a hydrogen atom, C_1-6Alkyl group or Ra
Rb Rc represents a Si group, wherein Ra, Rb and Rc are the same or
Differently, C_1-6Alkyl group, C_3-8Cycloalkyl
Represents a phenyl group or a phenyl group. R^Three, R^FourAre independent
Hydrogen atom, cyano group, halogen atom, C_1-6Archi
Group or C_1-6X represents an alkoxycarbonyl group, and X is
Represents a carbonyl group or a sulfonyl group, and Ar is a substituent
Represents a divalent aromatic group which may have
Represents 1. ), An asymmetric carbon on the piperazine ring
An optically active piperazine derivative having an atom is subjected to suspension polymerization or
Is a compound represented by the general formula (2):

[0026]

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Where R¹Is a hydrogen atom_,C_1-6Archi
Or an optionally substituted C _7-10Aralkyl group
And R^TwoIs a hydrogen atom, C_1-6Alkyl group or Ra
Rb Rc represents a Si group, wherein Ra, Rb and Rc are the same or
Differently, C_1-6Alkyl group, C_3-8Cycloalkyl
Represents a phenyl group or a phenyl group. R^Three, R^FourAre independent
Hydrogen atom, cyano group, halogen atom, C_1-6Archi
Group or C_1-6X represents an alkoxycarbonyl group, and X is
Represents a carbonyl group or a sulfonyl group, and Ar is a substituent
Represents a divalent aromatic group which may have
Represents 1 and n represents an integer of 1 to 1000. ) An oligomer or a polymer having a structural unit of the compound represented by
Method of manufacturing rimmers. (5) The following general formulas (1), (5) and
And (6)

[0028]

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Where R¹Is a hydrogen atom_,C_1-6Archi
Or an optionally substituted C _7-10Aralkyl group
And R^TwoIs a hydrogen atom, C_1-6Alkyl group or Ra
Rb Rc represents a Si group, wherein Ra, Rb and Rc are the same or
Differently, C_1-6Alkyl group, C_3-8Cycloalkyl
Represents a phenyl group or a phenyl group. R^Three, R^FourAre independent
Hydrogen atom, cyano group, halogen atom, C_1-6Archi
Group or C_1-6Represents an alkoxycarbonyl group;⁶,
R⁷, R⁸, R⁹, R^TenAnd R¹¹Are independent
And a hydrogen atom or C_1-6Represents an alkyl group;^FiveIs the water
Elementary atom, C_1-6Alkyl group, C_1-6Alkoxy group or ha
X represents a carbonyl group or a sulfonyl
And Ar represents a divalent group which may have a substituent.
Represents an aromatic group, and s represents 0 or 1. )
A compound represented by the following general formula,
(2), (3) and (4)

[0030]

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(Wherein, R ^{1 to} R ¹¹ , X, Ar, s, n,
m and l represent the same meaning as described above. A method for producing a copolymer having a structural unit of a compound represented by the formula:

The first invention of the present application is a monomer constituting the structural unit of the asymmetric polymer catalyst of the second invention of the present application. A second invention is an asymmetric polymer catalyst containing the optically active piperazine derivative as a constitutional unit. A third invention is an asymmetric polymer catalyst comprising the optically active piperazine derivative, styrene derivative and divinylbenzene derivative as constituent components. The fourth invention specifies the method for producing an asymmetric polymer catalyst according to the second invention. Further, a fifth invention specifies a method for producing an asymmetric polymer catalyst according to the third invention.

According to the present invention, as an asymmetric synthesis catalyst, particularly as an asymmetric reduction catalyst, separation from the reaction product is easy, the catalyst can be reused, and catalyst activity and asymmetric yield are reduced. The present invention provides a polymer asymmetric catalyst which can obtain an effect far superior to that of the monomer composed of and can be produced at low cost.

[0034]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. In the general formula (1) of the compound of the present invention, R ¹
Is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s- butyl, t- butyl, pentyl and its isomers, C _1-6 alkyl group such as hexyl and its isomers, or benzyl Represents a C _7-10 aralkyl group such as a group, α-methylbenzyl group, phenethyl group and the like. Further, the C _7-10 aralkyl group may have a substituent at any position of the benzene ring.

Examples of such a substituent include a C _1-6 alkyl group such as a nitro group, a cyano group and a methyl group;
Examples thereof include a halogen atom such as a _1-6 alkoxy group, fluorine, and chlorine. Further, the C _7-10 aralkyl group may have a plurality of the same or different substituents.

[0036] R ² is a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s- butyl, t- butyl, pentyl and its isomers, C _1-6 alkyl, such as hexyl and its isomers Group or Ra R
b represents a group represented by Rc Si, and Ra, Rb, and Rc represent
The same or different, and represents a C _1-6 alkyl group, a C _3-8 cycloalkyl group or a phenyl group.

In the above, Ra, Rb and Rc are the same or different and are each a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,
C _1-6 alkyl groups such as pentyl and hexyl groups; C _3-8 such as cyclopropyl, cyclopentyl and cyclohexyl groups
Represents a cycloalkyl group or a phenyl group.

The aforementioned Ra, Rb and Rc are preferably C
_{It is a 1-6} alkyl group, more preferably, R ² is a hydrogen atom, a trimethylsilyl group or a t-butyldimethylsilyl group.

R ³ and R ⁴ each independently represent a hydrogen atom, a cyano group, a halogen atom such as fluorine or chlorine, a C _1-6 alkyl group such as methyl or ethyl, or a methoxycarbonyl, ethoxycarbonyl group or the like. Represents a C _1-6 alkoxycarbonyl group. R ^{6 to} R ¹¹ are each independently
Represents a hydrogen atom or a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, and hexyl. Of these,
R ³ , R ⁴ , R ^{6 to} R ¹¹ are preferably a hydrogen atom or a methyl group.

R ⁵ is a hydrogen atom, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl or hexyl group, a methoxy, ethoxy, propoxy or isopropoxy group. C
Represents a _1-6 alkoxy group or a halogen atom such as fluorine, chlorine, and bromine. X represents a carbonyl group or a sulfonyl group.

Ar represents a divalent aromatic group. In the present invention, the aromatic group means a group of a cyclic compound having a wide aromaticity. Examples of such a divalent aromatic group include a group represented by the following formula (18).

[0042]

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Further, the aromatic group may have a substituent at any position of the aromatic ring. Examples of such a substituent include halogen atoms such as fluorine, chlorine, and bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
and C1-4 alkyl groups such as s-butyl and t-butyl groups, and _C1-4 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and t-butoxy groups. Further, the aromatic group may have a plurality of the same or different substituents.

The monomer (ie, the polymerizable monomer to be reacted with the optically active piperazine derivative) used for producing the compound represented by the general formula (1) includes at least a vinyl group (or a substituted vinyl group) and a carbonyl group in the molecule. There is no particular limitation as long as the compound has a group or a sulfonic acid group.

As such a polymerizable monomer, for example,
4-vinylbenzenesulfonic acid, 3-methyl-4-vinylbenzenesulfonic acid, 2-methyl-4-vinylbenzenesulfonic acid, 3-chloro-4-vinylbenzenesulfonic acid, 2-chloro-4-vinylbenzenesulfonic acid , 3
Vinylbenzenesulfonic acids such as -methoxy-4-vinylbenzenesulfonic acid, 2-methoxy-4-vinylbenzenesulfonic acid, and 4- (1-propenyl) sulfonic acid;
4-vinyl-1-naphthalenesulfonic acid, 4-vinyl-
3-methyl-1-naphthalenesulfonic acid, 4-vinyl-
2-chloro-1-naphthalenesulfonic acid, 5-vinyl-
1-naphthalenesulfonic acid, 5-vinyl-3-methyl-
1-naphthalenesulfonic acid, 5-vinyl-2-methyl-
1-naphthalenesulfonic acid, 5-vinyl-6-chloro-
Vinyl naphthalene sulfonic acids such as 1-naphthalene sulfonic acid,

Acrylic acids such as acrylic acid, methyl acrylate and ethyl acrylate, methacrylic acids such as methacrylic acid, methyl methacrylate and ethyl methacrylate, and unsaturated acids such as maleic acid, maleic anhydride, itaconic acid and itaconic anhydride Carboxylic acid, vinyl sulfonic acid and the like can be mentioned.

Of these compounds, in the present invention, use of vinylbenzene sulfonic acids and vinyl naphthalene sulfonic acid is preferred from the viewpoint of handleability and availability.

The polymerizable monomer capable of forming a copolymer by copolymerizing with the compound represented by the general formula (1) includes a styrene derivative represented by the general formula (5) and / or
Alternatively, a divinylbenzene derivative represented by the general formula (6) can be given.

Examples of the styrene derivative represented by the general formula (5) include styrene, o-methylstyrene,
p-methylstyrene, α-methylstyrene, p-ter
t-butylstyrene, p-methoxystyrene, pn-
Butoxystyrene, p-sec-butoxystyrene, p
-Tert-butoxystyrene, p-tert-butoxy-α-methylstyrene and the like.

The divinylbenzene derivatives represented by the general formula (6) include 1,3-divinylbenzene, 1,3-divinyl-2-methylbenzene, and 1,3-divinylbenzene.
Divinyl-4-methylbenzene, 1,3-divinyl-2
-Chlorobenzene, 1,3-divinyl-4-chlorobenzene, 1,4-divinylbenzene, 1,4-divinyl-
Examples thereof include 3-chlorobenzene and 1,4-divinyl-3-methylbenzene.

Further, in the present invention, the compound represented by the general formula (1) may be copolymerized with another polymerizable monomer, or the compound represented by the general formula (1), the compound represented by the general formula (5) ) And / or the compound represented by the general formula (6) can be copolymerized by further blending another polymerizable monomer.

Examples of such a polymerizable monomer include, for example,
Olefins such as ethylene, propylene, butene, vinyl chloride, vinylidene chloride, vinyl acetate, methyl vinyl ketone, vinyl naphthalene, vinyl pyridine, vinyl pyrrolidone, and other vinyl compounds, acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate Such as acrylates, methyl methacrylate, methacrylates such as ethyl methacrylate, 1,3-butadiene,
Isoprene, 2,3-dimethyl-1,3-butadiene,
Conjugated dienes such as 1,3-pentadiene, 2-methyl-1,3-pentadiene and 1,3-hexadiene; unsaturated carboxylic acids such as maleic acid and itaconic acid; and unsaturated carboxylic acids such as maleic anhydride and itaconic anhydride. Acid anhydrides, acrylamide, acrylonitrile and the like can be mentioned.

Production of Compound (1) The compound represented by the general formula (1) can be produced, for example, as follows. (A) Preparation of compound where X = SO ₂

[0054]

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(Wherein M represents a hydrogen atom, an alkali metal or an alkaline earth metal, hal represents a halogen atom, R ^{1 to} R ⁴ have the same meanings as described above, and s represents 0 or 1
Represents Among the compounds represented by the general formula (1), the compound wherein X is a sulfonyl group is obtained by reacting a compound or a salt represented by the general formula (10) with a halogenating agent in an inert solvent. The sulfonyl halide (11) can be produced by reacting the optically active piperazine derivative represented by the general formula (12) in the presence of a base.

As the halogenating agent, thionyl chloride, sulfuryl chloride, tinyl bromide, phosgene, oxalyl chloride and the like can be used.

The solvent that can be used in the halogenation reaction is not particularly limited as long as it does not inhibit the reaction. For example, N, N-dimethylformamide (DM
F), amides such as N, N-dimethylacetamide (DMA), aromatic hydrocarbons such as benzene and toluene, and halogenated solvents such as dichloromethane, chloroform and carbon tetrachloride. Further, a mixed solvent of these can also be used.

This halogenation reaction proceeds smoothly in a temperature range from -10 ° C. to the boiling point of the solvent used, but the resulting sulfonyl halide is generally unstable and difficult to isolate. It is preferable to use it for the next reaction without isolation.

Examples of the compound or salt represented by the general formula (10) as a raw material include 4-vinylbenzenesulfonic acid, 4-vinylbenzenesulfonic acid sodium salt and 4-vinylbenzenesulfonic acid.
Alkali metal salts of 4-vinylbenzene sulfonic acid such as potassium vinyl benzene sulfonic acid, 4-vinyl naphthalene sulfonic acid such as 4-vinyl naphthalene sulfonic acid, sodium salt of 4-vinyl naphthalene sulfonic acid and potassium salt of 4-vinyl naphthalene sulfonic acid Alkali metal salt of acid, 2-vinylpyridine-5-sulfonic acid, alkali metal salt of 2-vinylpyridine-5-sulfonic acid, 5-vinylpyridine-2-sulfonic acid, 5-vinylpyridine-2
Alkali metal salts of sulfonic acid, 2-vinylthiophen-5-sulfonic acid, alkali metal salts of 2-vinylthiophen-5-sulfonic acid, vinylsulfonic acid, alkali metal salts of vinylsulfonic acid, and the like can be used.

The following reaction between the piperazine derivative (12) and the sulfonyl halide (11) is carried out in an inert solvent in the presence of a base. Bases used in this reaction include triethylamine, diisopropylethylamine,
Organic bases such as pyridine, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, sodium methoxide, sodium ethoxide, magnesium ethoxide,
Metal alkoxides such as potassium t-butoxide, and carbonates such as sodium carbonate and potassium carbonate can be used.

The solvent that can be used is not particularly limited as long as it is an inert solvent. For example, halogenated solvents such as dichloromethane, chloroform and carbon tetrachloride, and ethers such as tetrahydrofuran (THF) and diethyl ether Examples include system solvents, amides such as DMF and DMA, aromatic hydrocarbons such as benzene and toluene, esters such as ethyl acetate, dimethyl sulfoxide, and acetonitrile. The reaction proceeds smoothly in a temperature range from −10 ° C. to the boiling point of the solvent used. (B) Preparation of compound where X = CO

[0062]

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(Wherein M ′ represents a hydrogen atom, an alkali metal or an alkaline earth metal, hal ′ represents a halogen atom, R ^{1 to} R ⁴ represent the same meaning as described above, and s represents 0 or 1 Represents.)

Among the compounds represented by the general formula (1), those wherein X is a carbonyl group are represented by the general formula (13)
Is reacted with a halogenating agent in an inert solvent to give an acid halide (14), and then the optically active piperazine derivative represented by the general formula (12) is added in the presence of a base. It can be manufactured by acting. As the base and the solvent that can be used in the reaction, the same ones as those listed as those that can be used in the case of producing a compound in which X is SO ₂ can be used.

Examples of the compound or salt represented by the general formula (13) as a raw material include 4-vinylbenzoic acid, 4-vinylbenzoic acid sodium salt, 4-vinylbenzoic acid potassium salt and the like. Alkali metal salts of acids, alkali metal salts of 4-vinylnaphthalenecarboxylic acid such as 4-vinylnaphthalenecarboxylic acid, sodium 4-vinylnaphthalenecarboxylate, potassium 4-vinylnaphthalenecarboxylate, 2-vinylpyridine-5- Carboxylic acid, 2
An alkali metal salt of -vinylpyridine-5-carboxylic acid,
5-vinylpyridine-2-carboxylic acid, alkali metal salt of 5-vinylpyridine-2-carboxylic acid, 2-vinylthiophen-5-carboxylic acid, 2-vinylthiophen-5
-Alkali metal salts of carboxylic acids, acrylic acid, alkali metal salts of acrylic acid, methacrylic acid, salts of methacrylic acid and the like can be used.

Examples of the compound represented by the general formula (1) obtained as described above are shown in Tables 1 to 6 below.

[0067]

[Table 101]

[0068]

[Table 102]

[0069]

[Table 103]

[0070]

[Table 104]

[0071]

[Table 105]

[0072]

[Table 106]

[0073]

[Table 107]

[0074]

[Table 108]

[0075]

[Table 201]

[0076]

[Table 202]

[0077]

[Table 203]

[0078]

[Table 204]

[0079]

[Table 205]

[0080]

[Table 206]

[0081]

[Table 207]

[0082]

[Table 208]

[0083]

[Table 301]

[0084]

[Table 302]

[0085]

[Table 303]

[0086]

[Table 304]

[0087]

[Table 305]

[0088]

[Table 306]

[0089]

[Table 307]

[0090]

[Table 308]

[0091]

[Table 401]

[0092]

[Table 501]

[0093]

[Table 601]

[0094]

[Table 701]

[0095]

[Table 702]

[0096]

[Table 703]

[0097]

[Table 704]

[0098]

[Table 705]

[0099]

[Table 706]

[0100]

[Table 707]

[0101]

[Table 708]

Production of Asymmetric Polymer Catalyst The polymer asymmetric catalyst of the present invention can be obtained by polymerizing the compound represented by the general formula (1) alone or by combining the compound represented by the general formula (1) with another compound. Can be produced by copolymerizing with a polymerizable monomer of In the case of copolymerization of the compound represented by the general formula (1) with another polymerizable monomer, the compound represented by the general formula (1) is copolymerized with the styrene derivative and / or divinylbenzene. Is preferred.

The asymmetric polymer catalyst of the present invention can be produced by using known polymerization methods such as solution polymerization and suspension polymerization.

In the case of suspension polymerization, the optically active piperazine derivative (1) and another polymerizable monomer are suspended in water to which a stabilizer has been added, if desired, together with a radical initiator.
The reaction is carried out at 40 ° C. to 100 ° C. for 1 hour to 2 days under normal pressure.

The stabilizer used here includes polyvinyl alcohol, methyl cellulose, carboxymethyl cellulose, polyacrylate and the like.

The radical initiator is added when a radical polymerizable monomer is used.
2′-azobis (2,4-dimethylvaleroniloryl),
An azo compound such as 2,2'-azobisisobutyronitrile, a peroxide such as benzoyl peroxide, cumene hydroperoxide, or the like can be used.

In the case of suspension polymerization, the obtained polymer is particularly preferable because it can be obtained as a bead-like (bulk) substance and has excellent handling properties and reactivity.

In the case of solution polymerization, the optically active piperazine derivative (1), another polymerizable monomer and, if desired, a radical initiator are mixed together in the presence of an organic solvent and polymerized, or an inert organic solvent is used. It can be carried out by dropping some or all of the above components in a solvent.

Examples of the organic solvent that can be used here include toluene, xylene, chloroform, methylene chloride, 1,2-dichloroethane, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, butyl acetate, dimethylformamide, tetrahydrofuran and the like. .

The radical initiator is added when a radical polymerizable monomer is used. Examples of the radical initiator include 2,2'-azobis (2,4-dimethylvaleronirolyl) and 2,2'-azo Azo compounds such as bisisobutyronitrile and peroxides such as benzoyl peroxide and cumene hydroperoxide can be used.

The polymerization conditions are not particularly limited, but may be from 40 ° C. to 1 ° C. under normal pressure and optionally under an inert gas atmosphere such as nitrogen gas.
By reacting at 00 ° C. for 1 hour to 2 days, a target polymer can be obtained.

When a radically polymerizable monomer is used, it can be polymerized under irradiation with light such as ultraviolet rays in addition to the radical polymerization initiator.

Although the degree of polymerization of the polymer of the present invention is not particularly limited, it is usually in the range of about 10 to 1,000.

Addition of the respective components when the compound represented by the general formula (1) is copolymerized with the compound represented by the general formula (2) and the compound represented by the general formula (3) The ratio is usually 5 to 30 mol% of the compound represented by the general formula (1), 50 to 90 mol% of the compound represented by the general formula (2), and represented by the general formula (3). Of the compound is about 1 to 20 mol%.

The polymer obtained as described above can be used as a catalyst for asymmetric synthesis, for example, a catalyst for an asymmetric reduction reaction as described below.

The catalytic reaction is carried out by suspending the polymer asymmetric catalyst of the present invention in a suitable solvent and adding appropriate amounts of a reaction substrate and a reducing agent to the system.

After the end of the reaction, the polymer according to the invention can be practically completely separated from the reactants by simple methods, for example by centrifugation, filtration, whereby the recovered catalyst can be reused.

[0118]

The present invention will be described in more detail with reference to the following examples, which should not be construed as limiting the invention thereto. The structure of the compound was determined by NMR, IR, MS and the like. The molecular weight of the polymer was measured by GPC (gel permeation chromatography).

Example 1 (Synthesis of chiral monomer) 2- (t-butyldimethylsilyloxymethyl) -4-
Synthesis of (4-vinyltosyl) piperazine (18)

[0120]

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To 2.63 g (12.8 mmol) of sodium styrenesulfonate (15), 6.5 of thionyl chloride was added.
The mixture was added under ice-cooling and stirred for 10 minutes. Thereafter, 3.5 ml of DMF was added under ice-cooling, the temperature of the reaction system was raised to room temperature, and the mixture was further stirred for 8 hours. After completion of the reaction, the reaction solution was poured into ice water with slow stirring, and ether (60 ml ×
Extracted in 3). After drying the organic layer over magnesium sulfate,
The solvent was distilled off under reduced pressure to obtain 2.42 g of 4-vinylphenylsulfonyl chloride (16). 94% yield.

Then, under a nitrogen atmosphere, 2- (t-butyldimethylsilyloxymethyl) piperazine (17)
2.89 g (12 mmol) and 4.5 of triethylamine
5 g (45 mmol) were dissolved in 15 ml of distilled chloroform. While stirring under ice-cooling, 4-vinylphenylsulfonyl chloride (16) obtained earlier was 2.4.
2 g (12 mmol) of distilled chloroform (15 ml)
The solution was slowly added dropwise, and after the addition was completed, an additional 12
Stirred for hours.

After the reaction was stopped by adding 40 ml of water to the reaction mixture, the mixture was extracted with chloroform (60 ml × 3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 5) to give 2- (t-butyldimethylsilyloxymethyl)-
3.4- (4-vinyltosyl) piperazine (18)
0 g was obtained. Yield 70%.

¹ H-NMR of compound (18) (CDCl
₃ , δppm): 0.02 (s, 6H), 0.88 (s, 9H), 1.79 (bs,
1H), 2.08 (m, 1H), 2.35 (m, 1H), 2.92 (m, 2H), 3.06
(m, 1H), 3.43 (m, 1H), 3.58 (m, 3H), 5.45 (d, 1H), 5.
89 (d, 1H), 6.77 (dd, 1H), 7.53 (d, 2H), 7.70 (d, 2H)

Example 2 (Suspension copolymerization)

[0126]

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2- (t-butyldimethylsilyloxymethyl) -4- (4-vinyltosyl) obtained in Example 1
3.25 g (8 mmol) of piperazine (18) was dissolved in 3 ml of benzene, and 3.33 g of styrene (19) was added thereto.
g (32 mmol), divinylbenzene (20) 0.1
0 g (0.8 mmol) and 2,2 as a polymerization initiator
2'-azobis (2,4-dimethylvaleronitrile)
(21) 0.13 g (0.5 mmol) was added (this solution is referred to as “mixed benzene solution”).

Next, the mixed benzene solution was added to 300
The solution was added dropwise to 0.2 ml of a 0.2% aqueous solution of povar under ice-cooling, and the stirring was continued after the addition was completed. After confirming with a microscope that the suspension containing the monomer and the polymerization initiator was uniformly dispersed in water, the mixture was further heated and stirred at 80 to 85 ° C. for 48 hours. The produced polymer was sieved to remove non-beaded polymer, and then washed repeatedly with water, THF and methanol. This is heated at 40 ° C. under reduced pressure for 2 hours.
Dried for 4 hours, beaded solid substance (beaded polymer)
5.62 g was obtained. This is the desired polymer. Yield 84%.

Example 3 (Solution polymerization)

[0130]

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40 ml of THF was placed in a sealable glass container having a predetermined size, and 2- (t-) obtained in Example 1 was obtained.
2.62 g (6.5 mm) of butyldimethylsilyloxymethyl) -4- (4-vinyltosyl) piperazine (18)
ol), 3.38 g (32.5 mmol) of styrene (19)
l) and 0.13 g (0.5 mmol) of 2,2′-azobis (2,4-dimethylvaleronitrile) (21) were dissolved, and the glass container containing these was sealed.

Next, after heating the glass tube at 60 ° C. for 48 hours, the glass tube was opened, and the reaction solution was added to a large excess of methanol to obtain a precipitate. The precipitate was washed with methanol and dried to obtain 3.79 g of a white powdery solid substance. 63% yield. The number average molecular weight (M
n) is 16,100 and the weight average molecular weight (Mw) is 2
6,500.

Example 4 (Production of SIP polymer) 5.56 g of the beaded polymer obtained in Example 2 was added to TH
After adding 35 ml of F and swelling, n-tetraammonium fluoride (1.0 M, 10.1 ml) was added, and the mixture was slowly stirred at 50 ° C for 20 hours. This was repeatedly washed with water, THF, and methanol, and dried under reduced pressure at 40 ° C. for 24 hours to obtain a polymer in which the t-butyldimethylsilyl group was desilylated (this is referred to as “SIP polymer”). Was.

[0134]

The following is an application example of asymmetric reduction using the asymmetric polymer catalyst of the present invention obtained as described above. In the following chemical formulas, the asterisk indicates an asymmetric carbon atom.

Application Example 1 (Asymmetric reduction of acetophenone o-methyl oxime)

[0136]

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Under a nitrogen stream, 5.99 g of SIP polymer
Was swelled with anhydrous THF (25 ml), and borane was added.
Dimethyl sulfide complex THF solution (10 M solution)
66 ml were added. The mixture was heated to 50 ° C. and stirred slowly at the same temperature for 15 hours. Thereafter, excess borane was distilled off under reduced pressure together with THF. Add new anhydrous TH
F20 ml and acetophenone o-methyl oxime (2
0) 0.40 g (2.68 mmol) was added, and the mixture was slowly stirred under nitrogen for 1 hour. 0.44 ml of a borane-dimethylsulfide complex THF solution (10 M solution) was added thereto, and the mixture was slowly stirred at room temperature for 24 hours.

After completion of the reaction, the reaction was stopped by adding 2N-HCl to the reaction solution, and the polymer was separated by filtration.
Was distilled off under reduced pressure. After washing the remaining acidic aqueous layer with ethyl acetate, the aqueous layer was neutralized with aqueous ammonia and extracted with ethyl acetate (50 ml × 3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1-phenylethylamine (21). After the product was subjected to trifluoroacetylation treatment, the optical purity of the amine was measured by gas chromatography (GC) using a chiral capillary column. From the result of the optical rotation measurement, it was found that the product was (R) -form. Yield 50%, optical purity 96% ee.

This reaction is a reduction reaction in which a hydrogen atom is added to the C = N bond of acetophenone o-methyl oxime. In this case, borane (BH) is added to the SIP polymer (22).
₃ ) reacts to form a 5-membered ring with a boron atom (B), a nitrogen atom (N) of a piperazine ring of the SIP polymer (22) and an oxygen atom (O) of a hydroxymethyl group as shown below. It is considered that a reaction intermediate (23) consisting of an oxazaborolidine ring) is produced.

[0140]

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Therefore, it is considered that the hydrogen atom is selectively added from a specific direction, and the asymmetric reduction reaction proceeds.

Application Example 2 (Reuse of Polymer Asymmetric Catalyst) Using the catalyst polymer used in Application Example 1, the same reaction as in Application Example 1 was carried out. Yield 58%. Further, as a result of measuring the optical purity of the reaction product in the same manner as in Application Example 1, 98% was obtained.
ee. This indicates that the polymer asymmetric catalyst of the present invention can be used repeatedly.

Reference Example 1 In the application example 1, instead of using the SIP polymer,
Optically active piperidine compound corresponding to the following raw material monomer (24)

[0144]

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An asymmetric reduction reaction was performed in the same manner as in Application Example 1 except that (wherein * represents an asymmetric carbon atom). The reaction was performed at room temperature and 50 ° C. As a result, although the reduction reaction did not proceed at room temperature, the reaction proceeded when heated to 50 ° C., and the desired 1-phenylethylamine was formed. Obtained in 50% yield. The obtained 1-
The optical purity of phenylethylamine was 84% ee. Table 8 shows the results of the asymmetric reduction reaction in the same manner.

[0146]

[Table 8]

As is evident from Table 7, the asymmetric polymer catalyst of the present invention has the ability to reduce acetophenone o-methyl oxime even at room temperature, and has excellent catalytic ability for asymmetric reduction. On the other hand, when the piperidine compound corresponding to the raw material monomer was used, the reduction reaction did not proceed at room temperature.

As described above, the compound of the present invention is a monomer for producing a novel polymer asymmetric catalyst and an asymmetric polymer catalyst having excellent asymmetric reduction ability.

The polymer asymmetric catalyst of the present invention can be easily separated from the reaction product, and can be reused.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C08F 2/06 C08F 2/06 2/18 2/18 12/14 12/14 16/36 16/36 22 / 40 22/40 28/02 28/02 28/06 28/06 212/04 212/04 212/34 212/34 // B01J 31/06 B01J 31/06 Z C07M 7:00 F term (reference) 4C063 AA01 CC12 CC92 DD34 EE05 4G069 AA08 AA09 BA21A BA21B BE19A BE20A BE22A BE22B CB57 4J011 HA03 JA06 JA07 JA08 JB26 4J100 AB00P AB02Q AB03Q AB04Q AB07P AB07Q AB15R AB16R AP01P AQ06P BA03P BAQBAPBAQP FA21 JA15

Claims (5)

[Claims] 1. A compound of the general formula (1)(Where R¹Is a hydrogen atom, C_1-6Alkyl group or substitution
C optionally having a group _7-10Represents an aralkyl group,^TwoIs a hydrogen atom, C_1-6Alkyl group or Ra Rb Rc
Represents a Si group, and Ra, Rb and Rc are the same or different
And C_1-6Alkyl group, C_3-8Cycloalkyl group or
Represents a phenyl group. R^Three, R^FourIs independently hydrogen
Atom, cyano group, halogen atom, C_1-6An alkyl group or
C_1-6X represents a carbonyl group or a sulfonyl group; Ar represents a divalent aromatic group which may have a substituent;
And s represents 0 or 1. ), Piperazine
Derivation of optically active piperazine having an asymmetric carbon atom on the ring
body. 2. A compound of the general formula (2)(Where R¹Is a hydrogen atom, C_1-6Alkyl group or substitution
C optionally having a group _7-10Represents an aralkyl group,^TwoIs a hydrogen atom, C_1-6Alkyl group or Ra Rb Rc
Represents a Si group, and Ra, Rb and Rc are the same or different
And C_1-6Alkyl group, C_3-8Cycloalkyl group or
Represents a phenyl group. R^Three, R^FourIs independently hydrogen
Atom, cyano group, halogen atom, C_1-6An alkyl group or
C_1-6X represents a carbonyl group or a sulfonyl group; Ar represents a divalent aromatic group which may have a substituent;
And s represents 0 or 1, and n represents an integer of 1 to 1000. Compound represented by)
An oligomer or polymer having the structural unit of 3. The general formula (2), the general formula (3) and the general formula (3)
Formula (4)(Where R¹Is a hydrogen atom, C_1-6Alkyl group or substitution
C optionally having a group _7-10Represents an aralkyl group,^TwoIs a hydrogen atom, C_1-6Alkyl group or Ra Rb Rc
Represents a Si group, and Ra, Rb and Rc are the same or different
And C_1-6Alkyl group, C_3-8Cycloalkyl group or
Represents a phenyl group. R^Three, R^FourIs independently hydrogen
Atom, cyano group, halogen atom, C_1-6 Alkyl group or C_1-6Represents an alkoxycarbonyl group,
R⁶, R⁷, R⁸, R⁹, R^TenAnd R¹¹Is German
Standing for a hydrogen atom or C_1-6Represents an alkyl group;^FiveIs a hydrogen atom, C_1-6Alkyl group, C_1-6Alkoki
X represents a carbonyl group or a sulfonyl group; and Ar represents a divalent aromatic group which may have a substituent.
S represents 0 or 1, n represents an integer of 1 to 1000, and m and l each independently represent an integer of 0 or 1 to 1000.
Represents a number, and m and l are not simultaneously 0. ) A copolymer having a structural unit of the compound represented by 4. A compound of the general formula (1)(Where R¹Is a hydrogen atom, C_1-6Alkyl group or substitution
C optionally having a group _7-10Represents an aralkyl group,^TwoIs a hydrogen atom, C_1-6Alkyl group or Ra Rb Rc
Represents a Si group, and Ra, Rb and Rc are the same or different
And C_1-6Alkyl group, C_3-8Cycloalkyl group or
Represents a phenyl group. R^Three, R^FourIs a hydrogen atom, a cyano group,
C_1-6Alkyl group or C_1-6An alkoxycarbonyl group
X represents a carbonyl group or a sulfonyl group, and Ar represents a divalent aromatic group which may have a substituent.
And s represents 0 or 1. ), A piperazine ring
Optically active piperazine derivative having asymmetric carbon atom on it
Is subjected to suspension polymerization or solution polymerization.
General formula (2)(Where R¹, R^Two, R^Three, R^Four, X, Ar and s are
Represents the same meaning as described above, and n represents an integer of 1 to 1000. Compound represented by)
For producing oligomers or polymers having the structural unit of
Law. 5. The following general formulas (1), (5) and (6):(Where R¹Is a hydrogen atom_,C_1-6Alkyl group or substitution
C optionally having a group _7-10Represents an aralkyl group,^TwoIs a hydrogen atom, C_1-6Alkyl group or Ra Rb Rc
Represents a Si group, and Ra, Rb and Rc are the same or different
And C_1-6Alkyl group, C_3-8Cycloalkyl group or
Represents a phenyl group. R^Three, R^FourIs independently hydrogen
Atom, cyano group, halogen atom, C_1-6An alkyl group or
C_1-6R represents an alkoxycarbonyl group;⁶, R⁷, R⁸, R⁹, R^TenAnd R¹¹Is German
Standing for a hydrogen atom or C_1-6Represents an alkyl group;^FiveIs a hydrogen atom, C_1-6Alkyl group, C_1-6Alkoki
X represents a carbonyl group or a sulfonyl group; and Ar represents a divalent aromatic group which may have a substituent.
And s represents 0 or 1. Copolymerization of the compound represented by
Characterized by the following general formulas (2), (3) and (4):(Where R¹~ R¹¹, X, Ar and s are as defined above.
And n represents an integer of 1 to 1000, and m and l each independently represent 0 or an integer of 1 to 1000.
Represents a number, and m and l are not simultaneously 0. )
For producing a copolymer having a structural unit of a compound to be obtained.