JPH11276193A - Preparation of optically active biaryl derivatives - Google Patents

Abstract

(57) [Problem] An object of the present invention is to provide a process for producing an optically active biaryl dialcohol derivative which is industrially advantageous and an enantiomeric acyl form thereof. SOLUTION: General formula (I) (Wherein ring Ar represents an optionally substituted 1-3-cyclic aromatic ring) in the presence of an enzyme capable of asymmetric acylation of a racemic biaryl dialcohol derivative represented by the formula: A method of producing an optically active biaryl dialcohol derivative and an enantiomer of the enantiomer thereof by reacting with an acyl donor. Also, a method for producing an optically active cyclic biaryl ketone derivative from the optically active biaryl dialcohol derivative or the enantiomer of the optically active biaryl dialketone derivative produced as described above.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing an optically active biaryl dialcohol derivative, a method for producing an enantiomerized acyl form thereof, and a method for producing an optically active cyclic biaryl ketone derivative using the same.

[0002]

2. Description of the Related Art An optically active cyclic biaryl ketone derivative having a C ₂ symmetric structure, such as ₂ -oxotrimethylene 1,1′-binaphthyl-2,2′-dicarboxylate, is known to have an axial chirality. For example, 2-oxotrimethylene 1,1′-binaphthyl-2,2′-dicarboxylate has two types of optical isomers as shown below.

[0003]

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It is known that such an optically active cyclic biaryl ketone derivative can be used as a suitable catalyst in an asymmetric epoxidation reaction of an olefin such as trans-stilbene (Journal of American Chemical Society (Journal of American Chemical Society)). J. Am. Chem. So
c. 118, 11311-11312, 1996.
Year).

[0005] Optically active phenylglycidic acid compounds are important synthetic intermediates of 1,5-benzothiazepine derivatives which are useful therapeutic agents for cardiovascular diseases. The optically active cyclic biaryl ketone derivative as described above can be used as a catalyst for an asymmetric epoxidation reaction in the synthesis of an optically active phenylglycidic acid compound,
It has been found to be very useful (Japanese Patent Application No. 09-17 / 1997)
1042).

[0006] As described above, the optically active cyclic biaryl derivative is a very useful compound, but as a production method thereof, an efficient method that can be used industrially has not been known. For example, Bulletin of Chemical Society of Japan (Bull. Chem.
Soc. Jpn. ), Vol. 61, 1032-1034
Page (1988) describes a method for optically resolving 1,1'-binaphthyl-2,2'-dicarboxylic acid using brucine, and the optically active 1,1'- obtained by this method is described. An optically active cyclic biaryl ketone derivative can be produced from binaphthyl-2,2'-dicarboxylic acid. However, brucine used as an optical resolving agent is toxic, and it is very difficult to use it as an industrial production method. There is also a problem that the yield of the optical resolution step is not sufficient.

As described above, as a method for producing an optically active cyclic biaryl derivative, it has been desired to develop a method which is safe and excellent in productivity.

[0008]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a method for producing an optically active biaryl dialcohol derivative and an enantiomer thereof, and to efficiently produce an optically active cyclic biaryl ketone derivative from these optically active compounds. It is to provide a method.

[0009]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that an enzyme produced by a certain microorganism can selectively acylate one optically active form of a racemic biaryl dialcohol derivative. The present inventors have found that optically active biaryl dialcohol derivatives and their enantiomers can be efficiently produced by asymmetric acylation with the enzyme, and completed the present invention. Further, they have found a method for producing an optically active cyclic ketone derivative using these optically active biaryl dialcohol derivatives or their enantiomers, and have completed the present invention.

That is, the present invention provides a compound represented by the general formula (I):

[0011]

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(Wherein ring Ar represents a 1- to 3-cyclic aromatic ring optionally having substituent (s)), one of the stereoisomers is selectively acylated. The present invention relates to a method for producing an optically active biaryl dialcohol derivative and an enantiomeric acyl form thereof by reacting with an acyl donor in the presence of an enzyme to be converted.

More specifically, a racemic biaryl dialcohol derivative represented by the general formula (I) is converted to a compound represented by the general formula (II) R ¹ COOR ² (R) in the presence of an enzyme which selectively acylates one stereoisomer. II) (wherein R ¹ represents an alkyl group or an aryl group, and R ² represents a hydrogen atom, an alkyl group, an alkenyl group, an alkanoyl group or an aroyl group), and reacted with an acyl donor represented by the general formula ( III)

[0014]

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(Where * represents the axial chirality of R or S, and the ring Ar has the same meaning as described above), and the axial chirality is reversed. General formula (IV)

[0016]

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(Provided that ** represents S or R axial chirality, R ³ represents a hydrogen atom or COR ¹ , and R ¹ and ring Ar have the same meaning as described above) The present invention relates to a method for producing an acyl form of an optically active biaryl dialcohol derivative. By separating and collecting these optically active substances from the reaction solution, desired optically active biaryl dialcohol derivatives and acyl enantiomers thereof can be produced.

Further, using the optically active biaryl dialcohol derivative obtained by the above-mentioned production method and its enantiomer acyl compound, a compound represented by the general formula (V):

[0019]

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(Wherein the symbols have the same meanings as described above), and a general formula (VI)

[0021]

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(Wherein the symbols have the same meanings as described above) can be produced.

[0023]

BEST MODE FOR CARRYING OUT THE INVENTION In the method of the present invention, compounds (III), (IV), (V) and (VI) have a structure in which the rotation of the ring Ar around the bond between the two rings Ar is steric. And having an axial chirality of R or S with respect to this bond axis (hereinafter referred to as R-form or S-form).
body).

In the compounds (III), (IV), (V) and (VI), the ring Ar is a 1-3 cyclic aromatic ring which may have a substituent. Examples of such a 1-3-ring aromatic ring include a benzene ring, a naphthalene ring, a naphthoquinone ring, an anthracene ring, an anthraquinone ring, a phenanthrene ring and the like, and among them, a naphthalene ring is preferable. The position of the bond between the two rings Ar is determined by the compounds (III), (IV), (V) and (VI)
The bond is not particularly limited as long as it produces axial chirality, but it is preferable to have another bond ortho to the bond connecting the two rings Ar.

As the substituent on the aromatic ring, for example, a halogen atom represented by a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, a nitro group, a methylsulfonyl group, a p-
An electron-withdrawing group such as a toluenesulfonyl group, a trifluoromethyl group, a cyano group, a methoxycarbonyl group, a methylsulfoxide group, a sulfonylamide group; and a carbon number of 1 to 4 represented by a methyl group, an ethyl group, a propyl group and a butyl group.
A lower alkoxy group having 1 to 4 carbon atoms represented by a lower alkyl group, a methoxy group, an ethoxy group, a propoxy group and a butoxy group; a carbon atom having a carbon number of 3 to 3 represented by a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group. And electron-donating groups such as aralkyl groups having 7 to 10 carbon atoms, such as 7 cycloalkyl groups, benzyl groups and phenethyl groups. Among these groups,
An electron-withdrawing group is preferable, and a halogen atom is particularly preferable.

A more specific ring Ar has the general formula:

[0027]

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Wherein R ^a and R ^b are each a hydrogen atom or a substituent, and R ^c and R ^d are groups satisfying the following conditions: (I) R ^c and R ^d are each a hydrogen atom or a substituent Or (II) R ^c and R ^d are bonded to each other to form a general formula:

[0029]

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(Wherein, R ^e , R ^f , R ^g and R ^h represent any of the following:

(A) two adjacent groups are bonded to each other to form a benzene ring which may be substituted together with two carbon atoms between them, and the other two groups are a hydrogen atom or a substituent; Or (b) each being a hydrogen atom or a substituent), or (III) R ^c and R ^d are bonded to each other to form a general formula:

[0032]

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(Wherein, R ⁱ , R ^j , R ^k and R ^m each represent a hydrogen atom or a substituent).

Here, the substituent in R ^{a to} R ^m includes a halogen atom represented by a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, a nitro group, a methylsulfonyl group, a p-toluenesulfonyl group, a trifluoro group. An electron-withdrawing group such as a methyl group, a cyano group, a methoxycarbonyl group, a methylsulfoxide group, a sulfonylamide group; a lower alkyl group having 1 to 4 carbon atoms represented by a methyl group, an ethyl group, a propyl group and a butyl group; , Ethoxy, propoxy and butoxy groups
C.sub.4 -C.sub.4-7 lower alkyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl represented by C.sub.3-7 cycloalkyl, benzyl and phenethyl groups represented by C.sub.7-10 aralkyl. And other electron donating groups. Among these groups, an electron-withdrawing group is preferable, and a halogen atom is particularly preferable.

In the present invention, the racemic biaryl dialcohol derivative represented by the general formula (I) used as the starting compound may be any one containing both R-form and S-form. Is not limited to those containing the same amount.

In the present invention, the acyl donor is not particularly limited as long as it can be subjected to an asymmetric acylation reaction by an enzyme, and the general formula (II) R ¹ COOR ² (II) (wherein R ¹ is an alkyl group Or an aryl group, and R ² represents a hydrogen atom, an alkyl group, an alkenyl group, an alkanoyl group or an aroyl group.

The alkyl group represented by R ¹ includes a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group,
Examples thereof include an alkyl group having 1 to 18 carbon atoms (linear or branched) such as a hexyl group, a heptyl group, an isopropyl group, a sec-butyl group and a tert-butyl group, and the aryl group includes a phenyl group and a naphthyl group. And the like, and a bicyclic aromatic ring. Among them, a linear alkyl group having 1 to 18 carbon atoms is preferable.

Examples of the alkyl group represented by R ² include the same as those described above. Examples of the alkenyl group include alkenyl groups having 2 to 8 carbon atoms (linear or branched) such as vinyl and isopropenyl. Examples of the alkanoyl group include an alkanoyl group having 2 to 8 carbon atoms (linear or branched) such as an acetyl group, a propionyl group, a butyryl group, and a hexanoyl group. And the like, wherein the aryl moiety is a one- or two-cyclic aromatic ring (phenyl group, naphthyl group, etc.). Among them, a hydrogen atom, an alkyl group, an alkenyl group having 2 to 8 carbon atoms, or an alkanoyl group having 2 to 8 carbon atoms is preferable, and a vinyl group is particularly preferable.

Preferred examples of such acyl donors include, for example, aliphatic carboxylic acids (such as myristic acid, lauric acid, and decanoic acid), aromatic carboxylic acids (such as benzoic acid), and carboxylic esters (acetic acid). Vinyl, vinyl butyrate, vinyl hexanoate, vinyl octanoate, isopropenyl acetate, etc.) and carboxylic anhydrides (butyric anhydride, valeric anhydride, benzoic anhydride, succinic anhydride, etc.).

Among them, particularly, fatty acid vinyl esters having 2 to 10 carbon atoms (vinyl acetate, vinyl propionate, vinyl butyrate, vinyl hexanoate, vinyl octanoate, vinyl decanoate, etc.) are obtained after acylation. , preferable in that radical R ² can be easily removed from the reaction system.

The enzyme used in the present invention may be any enzyme capable of asymmetrically acylating the biaryl dialcohol derivative represented by the general formula (I). As such an enzyme, for example, an enzyme (lipase, esterase, or the like) obtained from animal or plant tissues, cells, microorganisms, or the like can be used.

The use of a microorganism-derived enzyme is advantageous in that its preparation is easy. Examples of microorganisms that are enzymes are, for example, Penicillium (Penicium).
genus illium, genus Mucor, genus Pseudomonas, humicola (H
Microorganisms belonging to the genus Umicola, the genus Candida, the genus Serratia, and the like.

More specifically, for example, penicillium
Cyclopium (Penicillium cyclop)
ium), Mucor jabanicas (Mucor ja)
vanicus), Mucor Miehei (Mucor)
Miehei), Pseudomonas fluorescens (P
pseudomonas fluorescens), Pseudomonas cepacia (Pseudomonas c)
epasia), Humicola Ranuginosa (Humic)
ola lanuginosa, Candida cylindracea or Serratia marsessen
cescens).

In order to obtain an enzyme having the ability to selectively acylate the R-form of the biaryl dialcohol derivative represented by the general formula (I), penicillium (P
enicilium), Mucor
And microorganisms belonging to the genus Pseudomonas, the genus Humicola, and the like, more specifically, Penicillium cyclopium (Penici).
llium cyclopium, Mucor javanicus, Mucor miehei, Pseudomonas fl.
uorescens), Pseudomonas cepacia (Ps
eumondonas cepasia) or Humicola
Humicola lanuginos
a) and the like can be suitably used. Among these, microorganisms belonging to Humicola (Humicola lanuginosa)
a) is preferred.

In order to obtain an enzyme having the ability to selectively acylate the S-isomer of the biaryl dialcohol derivative represented by the general formula (I), a microorganism belonging to the genus Candida, Serratia or the like may be used. Is Candida cylindracea or Serratia marcescens (Serratia ma)
and the like can be suitably used. Among these, microorganisms belonging to the genus Serratia (Serratia marcescens)
s) is preferred.

Specific examples of enzymes derived from microorganisms of the genus Serratia include Serratia marcescens (Serratia).
marcescens) Sr41 strain (FERM BP-
487) (Japanese Unexamined Patent Publication No. 4-228070)
Publication, European Patent Publication No. 0446771, Journal of Fermentation and Bioengineering (Journal of Fermen)
Tation and Bioengineering
g), 75, 93-98, 1993, or 77, 152-158, 1994.

Microorganisms which are the origins of enzymes include wild strains,
The strain may be a mutant strain, or may be derived from these microorganisms by biotechnological techniques such as genetic recombination and cell fusion.

The commercially available enzymes capable of asymmetric acylation of the biaryl dialcohol derivative represented by the general formula (I) are shown in Tables 1 and 2 below. These commercially available enzymes can also be used as enzymes.

[0049]

[Table 1]

[0050]

[Table 2]

Among these, the enzymes that selectively acylate the (R) type isomer include lipase CE and lipase S
P523 and lipase SP526 are preferred, and CCL is preferred as the enzyme that selectively acylates the (S) type isomer.

The form of the enzyme is not particularly limited. In addition to a purified enzyme and a partially purified enzyme (crude enzyme), when it is derived from a microorganism, live cells of the microorganism, cultures, and processed products thereof (washed cells, Dried cells, culture supernatant, cell lysate, cell autolysate, cell extract, etc.), and when derived from animal or plant tissues or cells, tissue or cell extracts, etc. Can be used as needed.

Preparation of various forms of the enzyme can be carried out by a conventional method. For example, viable cells and cells, or culture supernatant can be obtained from a culture solution of microorganisms and cells by centrifugation or filtration. Further, washed cells can be obtained by washing the viable cells with physiological saline, and dried cells can be obtained by freeze-drying or acetone-drying the viable cells, the washed cells, and the like. In addition, live cells, washed cells, cells, etc. are treated with various physicochemical methods (for example, treatment with ultrasonic waves, French press, osmotic pressure, freeze-thawing, alumina destruction, lytic enzymes, surfactants or organic solvents). By treating with, the crushed cells and cells can be obtained, and an extract of the cells and cells can be obtained by removing solids from the crushed cells and cells by filtration or centrifugation. be able to. A partially purified enzyme or a purified enzyme can be obtained by fractionating and purifying from the fractions such as the extract by an ordinary method such as ammonium sulfate fractionation, ion exchange chromatography, gel filtration chromatography and the like.

Further, the enzyme can be used after being immobilized by a known method using, for example, a sulfur-containing polysaccharide gel such as carrageenan gel, polyacrylamide, alginate gel, agar gel, celite, a photo-crosslinkable resin and the like.

A method for screening an enzyme having asymmetric acylation ability by assaying the enzyme for asymmetric acylation ability can be carried out as follows. That is, a test sample containing an enzyme (an enzyme preparation, a culture of a microorganism, etc.) is added together with a substrate to perform an acylation reaction, and then the reaction solution is subjected to an optical isomer analysis column (eg, CHIRA manufactured by Daicel Corporation).
Analysis by high performance liquid chromatography (HPLC) using LCEL OD) and examination of the optical purity and the amount of unreacted substrate and product can determine whether or not asymmetric acylation activity is observed. it can.

In the present invention, asymmetric acylation is carried out in a suitable solvent using a racemic biaryl dialcohol derivative (I) as a reaction substrate in the presence of an enzyme which selectively acylates one stereoisomer. The reaction can be carried out by reacting a substrate with an acyl donor. By such an asymmetric acylation reaction, an optically active biaryl dialcohol derivative and its enantiomer can be obtained.

The charged concentration of the reaction substrate is usually 0.05-3.
It is preferably 0%, especially 1-20%.

The amount of the enzyme used is usually 1 to 1 g of substrate.
× 10 to 1 × 10 ⁵ U, especially 1 × 10 ² to 1 × 10 ⁴ U
Preferably, the olive oil-decomposing activity is determined.

The amount of the acyl donor is usually from 0.3 mol ratio to 8000 mol ratio, especially 0.5 m
It is preferable to set the ratio from the ol ratio to the 80 mol ratio. The reaction substrate and the acyl donor may be added all at once in the beginning, or may be supplied in several portions during the reaction.

The acyl form obtained by the asymmetric acylation reaction may be a monoacyl form or a diacyl form, but is preferably a monoacyl form, that is, a compound in which R ³ is a hydrogen atom in compound (IV). .

The solvent used for the asymmetric acylation reaction includes:
Any substance can be used as long as the substrate is dissolved or suspended, but an organic solvent is preferable. One type of solvent may be used, or two or more types may be used in combination.

Examples of the organic solvent include ethers such as tert-butyl methyl ether, isopropyl ether, diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane; Hydrogens; esters such as ethyl acetate, butyl acetate, and vinyl acetate;
Hydrophobic solvents such as butyl methyl ether, isopropyl ether, toluene and xylene are preferred. The reaction system desirably contains a small amount of water, preferably 0.001 to 5%, particularly preferably 0.01 to 1%, so that the reaction can be suitably performed. proceed. Water may be contained in the enzyme or in the solvent.

The reaction is carried out at room temperature or under heating, preferably for 1 hour.
It proceeds favorably at 0-80 ° C, especially at 25-50 ° C.

From the reaction mixture after the asymmetric acylation reaction, an optically active biaryl dialcohol derivative and its enantiomeric acyl compound can be collected and isolated.

The collection and isolation can be performed according to a conventional method. For example, after the enzyme is removed from the reaction solution by filtration or the like, if necessary, the solvent is distilled off, and the reaction solution is concentrated. Next, the desired optically active biaryl derivative can be separated by a purification method such as a fractional crystallization method utilizing a difference in solubility or a column chromatography method. In the case of performing separation by fractional crystallization, even when the optical purity of the optically active substance in the mixture obtained by the reaction is low, the difference in the solubility between the racemic form and the optically active substance is utilized to obtain an optically active substance during the crystallization process. There is an advantage that the purity can be increased.

The optically active biaryl dialcohol derivatives obtained by the asymmetric acylation reaction and the enantiomers thereof can be led to the corresponding optically active cyclic biaryl ketone derivatives (V) and (VI), respectively. That is, the optically active biaryl dialcohol derivative can be converted to an optically active cyclic biaryl ketone derivative (V) by subjecting it to an oxidation reaction and then to a cyclization reaction. Further, the enantiomer of the optically active biaryl dialcohol derivative is subjected to a hydrolysis reaction or the like to remove the acyl group to obtain an optically active biaryl dialcohol derivative.
By oxidizing and further subjecting it to a cyclization reaction, it can be converted to an optically active biaryl ketone derivative (VI). When a ketone derivative is produced from a dialcohol derivative, as compared with a case where a ketone derivative is produced from an acyl derivative, there are advantages in that the number of steps is reduced and the process is more efficient, and a decrease in yield can be prevented.

In the oxidation reaction of the optically active biaryl dialcohol derivative, the optically active biaryl dialcohol derivative can be directly oxidized to the optically active biaryl dicarboxylic acid derivative. Any of them can be carried out in a suitable solvent or without a solvent in the presence of an oxidizing agent.

As the solvent, any solvent can be used as long as it is inert to the reaction. For example, halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, dichloroethane; diethyl ether, tert-butylmethyl Ethers such as ether, isopropyl ether, tetrahydrofuran and dioxane; amides such as N, N-dimethylformamide; nitriles such as acetonitrile; hydrocarbons such as benzene, toluene, xylene and hexane can be preferably used. However, especially toluene is preferred.

The oxidizing agent used in the oxidation reaction for obtaining the optically active biaryl dialdehyde derivative from the optically active biaryl dialcohol derivative includes metal oxides such as manganese dioxide, pyridinium chlorochromate, and tetrapropylammonium parthenate-N-methylmorpholine oxide. Agent, oxalic acid dichloride dimethyl sulfoxide,
1,1,1-tris (acetyloxy) -1,1-dihydro-1,2-benziodoxol-3 (1H)-
Non-metal oxidizing agents such as on, among which manganese dioxide is particularly preferably used. As the oxidizing agent used for the oxidation reaction for obtaining the optically active biaryldicarboxylic acid derivative from the optically active biaryldialdehyde derivative, chlorite is used. Sodium, potassium permanganate, potassium dichromate, chromium oxide, ruthenium chloride-sodium periodate, ruthenium oxide, and the like.
In particular, sodium chlorite is preferably used. Also, directly from the optically active biaryl dialcohol derivative,
Examples of the oxidizing agent used in the oxidation reaction for obtaining the optically active biaryldicarboxylic acid derivative include potassium permanganate, potassium dichromate, chromium oxide, ruthenium chloride-sodium periodate, ruthenium oxide and the like.

The subsequent cyclization reaction is described in Journal of American Chemical Society (Journ).
al of American Chemical S
OCT.), Vol. 118, pp. 491-492 (19
96) Supplementary Materials (Suppl
elementary Material), dihydroxyacetone or a dimer thereof and iodide 2
-Chloro-1-methylpyridinium.

The step of removing the acyl group of the enantiomeric acyl form of the optically active biaryl dialcohol derivative can be carried out by a conventional method such as hydrolysis, aminolysis, or alcoholysis in an appropriate solvent or without a solvent using an acid or base. It can be performed in the presence or absence.

As the solvent, the same solvents as those used in the oxidation step can be used.

In carrying out the hydrolysis, the base may be an alkali metal hydride (eg, lithium hydride, sodium hydride, potassium hydride, etc.), an alkali metal hydroxide (eg, lithium hydroxide, sodium hydroxide, water Potassium oxide and the like, alkaline earth metal hydroxide (calcium hydroxide, barium hydroxide and the like), alkylamine (for example, triethylamine, N, N-diisopropyl-N-ethylamine and the like) and the like can be preferably used. As the acid, hydrochloric acid, sulfuric acid and the like can be suitably used.

When performing aminolysis, a primary amine such as ammonia, methylamine, ethylamine or the like as a base;
Secondary amines such as dimethylamine and diethylamine can be suitably used.

When alcoholysis is performed, the base may be
Tri-lower alkylamines (eg, triethylamine, diisopropylethylamine, etc.), pyridine, 4- (N,
N-dimethylamino) pyridine, aniline, N, N-dimethylaniline, 2,4,6-collidine, sodium hydroxide and the like can be suitably used.

The acyl group removal and oxidation reaction can be carried out under heating to cooling, preferably at 10 ° C.
~ 100 ° C, especially 20 ° C ~ 11 ° C.
It is preferably carried out at 0 ° C.

The optically active biaryl dialcohol derivative and the enantiomer of the enantiomer obtained by the asymmetric acylation reaction may be isolated and then used for the production of an optically active cyclic biaryl ketone derivative. Alternatively, an acyl group removal reaction, an oxidation reaction, and / or a cyclization reaction can be performed using the reaction solution after the asymmetric acylation reaction as it is. When the oxidation reaction is directly performed without separating the alcohol form and the acyl form, the ketone body, the alcohol form and the acyl form can be separated by the same method as described above. Since the ketone compound has good crystallinity, isolation can be performed more easily by performing separation by crystallization.

[0078]

EXAMPLES 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.

Embodiment 1

[0080]

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10 mg of the racemic compound (Ia), 2
ml of tert-butyl methyl ether, and 200 μl
The enzyme is added to 1 l of vinyl hexanoate and reacted at 30 ° C. for 24 hours. The residual amount of each isomer of alcohol and the amount of each isomer of hexanoyl in the reaction solution were determined by CHIR.
HP using ALCEL OD (manufactured by Daicel Chemical Industries)
Checked by LC. The results are shown in Table 3.

The HPLC conditions are as follows.

[Mobile phase] Hexane: ethanol = 60:
1 [Flow rate] 10 ml / min

[0084]

[Table 3]

Embodiment 2

[0086]

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Tert-butyl methyl ether 100 m
1.0 g of RS alcohol compound (compound 1) in 1
0 ml of vinyl acetate, 1.0 g of lipase SM (olive oil decomposition activity 1.96 × 10 5 U) and 50 μl of water are added, and the mixture is stirred and reacted at 30 ° C. for 24 hours. The reaction solution is filtered through filter paper, and the solvent in the filtrate is distilled off to obtain a residue. The residue was subjected to silica gel column chromatography to separate the alcohol form and the monoacetyl form, and 290 mg (yield: 29%) of 100% ee R alcohol form (compound 2) and 679 mg of 43% ee S acetyl form (compound 3)
(Yield: 60%).

Embodiment 3

[0089]

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(1) Toluene 1 of 500 mg of compound 2
5 g of manganese dioxide is added to the 0 ml solution,
Stir for 7 hours at 50-60 ° C for 1 hour. After filtering off the insoluble matter, the filtrate is concentrated under reduced pressure. The concentrated residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1).
Compound 4 was purified to 486.5 by purification in 0: 1).
mg (yield: 98.6%).

Oil EI-MS (m / z): 310 (M +) NMR (CDCl3, δ): 7.21-7.42 (m,
4H), 7.60-7.68 (m, 2H), 8.00-
8.23 (m, 6H), 9.62 (s, 2H).

(2) 26 mg of sodium dihydrogen phosphate was added to a solution of 100 mg of compound 4 in 1 ml of acetonitrile.
Add dihydrate and 0.08 ml of hydrogen peroxide and add 1 m of water
sodium chlorite (102 mg) dissolved in
Add dropwise at ° C. After stirring at 40 ° C. for 20 minutes, 6 mg of sodium sulfite is added at 25 ° C., and acetonitrile is distilled off under reduced pressure. The pH is adjusted to 1.0 with 2N hydrochloric acid and the product is extracted with ethyl acetate. The ethyl acetate solution is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. N-Hexane was added to the precipitated crystals, and the crystals were collected by filtration and dried by blowing air at 50 ° C for 17 hours to give 74.4 mg of Compound 5 (yield: 67.4).
%).

M. p. 194-198 DEG C. EI-MS (m / z): 342 (M @ +) NMR (CDCl3, .delta.): 7.04-7.08 (m,
2H), 7.18-7.26 (m, 2H), 7.44-
7.53 (m, 2H), 7.84-8.00 (m, 2
H), 8, 11-8.15 (m, 1H).

Embodiment 4

[0095]

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Compound 5 was prepared using the Journal of American Chemical Society (Journal of American Chemical Society).
American Chemical Society
y), Vol. 118, pp. 491-192 (1996), Supplementary Materials.
Compound 6 is obtained by treating according to the method of the present invention (ary Material).

Reference Example

[0098]

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Compound 7 (192 mg, 1.0 mmol)
After dissolving at room temperature in 1,2-dimethoxyethane 15ml, 4 × 10 ^- was added 4M disodium ethylenediaminetetraacetate salt solution 10 ml, and then Compound 6 (40
mg, 0.1 mmol) and cooled to 0 ° C. by an external bath. After that, 6.14 g of Oxone (10 mmo
l) and a mixture of 2.6 g (31 mmol) of sodium bicarbonate are added in six portions every hour. After the addition is complete,
After stirring for an hour, the obtained reaction mixture is poured into half-saturated saline and extracted with ether. The organic layer is washed with a saturated saline solution and then dried over anhydrous magnesium sulfate.

After drying, anhydrous magnesium sulfate was filtered off.
The solvent is distilled off from the filtrate. 9 ml of a 1: 8 (volume ratio) mixture of ethyl acetate and n-hexane is added to the obtained residue, and the mixture is stirred at room temperature for 1 hour.

The precipitated white powder was collected by filtration and dried under reduced pressure to recover the compound 6 (32 mg) (recovery rate: 8).
0% by weight).

On the other hand, the obtained filtrate (yield by HPLC:
91%) by flash column chromatography on silica gel (mobile phase: ethyl acetate: n-hexane = 1: 8).
(Volume ratio)) to obtain Compound 8 (135 mg, isolation yield: 65%). When the optical purity of this product was determined by HPLC, it was 81% ee.

[0103]

According to the method of the present invention, an optically active biaryl dialcohol derivative and an enantiomer thereof can be safely and efficiently produced by an asymmetric acylation reaction using an enzyme. it can.

Claims (19)

[Claims] 1. A compound of the general formula (I): (Wherein, ring Ar represents a 1-3-cyclic aromatic ring which may have a substituent) and an enzyme which selectively acylates one of the stereoisomers of the racemic biaryl dialcohol derivative A method for producing an optically active biaryl dialcohol derivative and an enantiomer thereof by reacting with an acyl donor in the presence of 2. An acyl donor represented by the general formula (II): R ¹ COOR ² (II) (where R ¹ represents an alkyl group or an aryl group, and R ² represents a hydrogen atom, an alkyl group, an alkenyl group, an alkanoyl And an optically active biaryl dialcohol derivative represented by the general formula (II)
I): embedded image (However, * indicates that the compound has an axial chirality of R or S, and the ring Ar has the same meaning as described above), and the enantiomer of the compound is represented by the general formula (I
V): embedded image (However, ** indicates that the compound has S or R axial chirality, R ³ indicates a hydrogen atom or COR ¹ , and R ¹ and ring Ar have the same meanings as described above.) The method of claim 1. 3. An enzyme that selectively acylates one stereoisomer is Penicillium.
Genus, Mucor, Pseudomonas (Ps
eudomonas, Humicola (Humicol)
The method according to claim 1 or 2, wherein the lipase or esterase is produced by a) a microorganism of the genus, Candida or Serratia. 4. The method according to claim 1, wherein an enzyme which selectively acylates the (R) type isomer is used. 5. An enzyme which selectively acylates the (R) type isomer is selected from the group consisting of Penicillium,
Genus Mucor, Pseudomonas (Pseu)
The method according to claim 3 or 4, which is a lipase or an esterase produced by a microorganism belonging to the genus domonas or Humicola. 6. An enzyme which selectively acylates the (R) type isomer is penicillium cyclopium (Penicil).
lium cyclopium, Mucor javanicus, Mucor miehei, Pseudomonas fluorescein
rescens), Pseudomonas cepacia (Pse
The method according to claim 5, which is a lipase or an esterase produced by a microorganism of Udomonas cepasia or Humicolalanuginosa. 7. The method according to claim 1, wherein an enzyme that selectively acylates the (S) type isomer is used. 8. The method according to claim 3, wherein the enzyme that selectively acylates the (S) type isomer is a lipase or an esterase produced by a microorganism of the genus Candida or Serratia. 9. An enzyme which selectively acylates the (S) type isomer is Candidacylindrasia (Candidac).
9. The method according to claim 8, which is a lipase or an esterase produced by a microorganism of Y. lindracea or Serratia marcescens. 10. A ring Ar is a benzene ring, a naphthalene ring,
The method according to any one of claims 1 to 9, which is a naphthoquinone ring, an anthracene ring, an anthraquinone ring or a phenanthrene ring. 11. A ring Ar having the general formula: Wherein R ^a and R ^b are each a hydrogen atom or a substituent,
R ^c and R ^d are groups satisfying the following conditions: (I) R ^c and R ^d are each a hydrogen atom or a substituent, or (II) R ^c and R ^d are bonded to each other to form a general formula : (Wherein, R ^e , R ^f , R ^g and R ^h represent any of the following: (a) two adjacent groups are bonded to each other and 2
A benzene ring which may be substituted together with two carbon atoms, and the other two groups are a hydrogen atom or a substituent, or (b) each is a hydrogen atom or a substituent) Or (III)
R ^c and R ^d are bonded to each other to form a general formula: (Wherein R ⁱ , R ^j , R ^k, and R ^m each represent a hydrogen atom or a substituent). 12. The method according to claim 1, wherein the ring Ar is a naphthalene ring.
2. The method according to 2. 13. The method according to claim 1, wherein R ¹ is a linear alkyl group having 1 to 18 carbon atoms. 14. The method according to claim 1, wherein R ² is a vinyl group.
The described method. 15. The method according to claim 1, wherein R ³ is a hydrogen atom.
The described method. 16. The method according to claim 1, wherein the optically active biaryl dialcohol derivative is separated and obtained. 17. The method according to claim 1, wherein the enantiomer of the optically active biaryl dialcohol derivative is separated and obtained. 18. Using the optically active biaryl dialcohol derivative obtained in claim 16, a compound represented by the general formula (V): (However, * represents that the compound has axial chirality of R or S, and ring Ar represents a 1 to 3 cyclic aromatic ring which may have a substituent). A method for obtaining a derivative. 19. An enantiomeric acyl form of the optically active biaryl dialcohol derivative obtained in claim 17,
General formula (VI) (However, ** represents having an axial chirality of S or R, and ring Ar represents a 1-3 cyclic aromatic ring which may have a substituent). A method for obtaining a ketone derivative.