JP2010037238A - Method for producing biaryl compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a biaryl compound having tyrosinase inhibitory activity, useful as a skin-lightening agent. <P>SOLUTION: The biaryl compound represented by formula (3) is produced by reacting a methyl 6-methoxybenzoate derivative, boronated at the 5-position in which a hydroxy group at the 2-position is protected with a fixed protective group, with a 6-methylbenzyl bromide derivative in which hydroxy groups at the 2-position and the 4-position are protected with fixed protective groups, followed by deprotecting the resultant product. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for producing a biaryl compound having tyrosinase inhibitory activity useful as a whitening agent.

  Skin darkening, spots, freckles, etc. are produced by tyrosine in the melanocytes that are increased or activated under the influence of hormonal secretion abnormalities or UV stimulation, and melanin is produced from tyrosine and released into the skin tissue. Caused by deposition.

  Therefore, various substances that inhibit the action of tyrosinase have been used or proposed in the field of cosmetics and foods in order to prevent the production of melanin by the above mechanism.

  For example, Patent Document 1 discloses a cosmetic containing an extract of Hanabiratake (scientific name: Sparassis crispa), which is an edible mushroom belonging to the genus Hanabiratake. In Patent Document 1, as a Hanabiratake extract having tyrosinase inhibitory activity and a whitening effect, a fraction extracted from Hanabiratake using chloroform, and a fraction extracted from Hanabiratake using ethanol, acetone and hexane Are listed.

JP 2005-281224 A

  As disclosed in Patent Document 1, many plant extracts such as mushrooms have been proposed as substances having tyrosinase inhibitory activity. However, at present, it has not been proposed to obtain a compound having tyrosinase inhibitory activity by a chemical synthesis method.

  Accordingly, an object of the present invention is to provide a method for producing a biaryl compound obtained by chemical synthesis of a biaryl compound having tyrosinase inhibitory activity useful as a whitening agent.

  In the present invention, the hydroxyl group at the 2-position is protected with a predetermined protecting group, and the 5-position is boronated.

［式中、（Ｐｒ１）は保護基を示す。］

[Wherein (Pr1) represents a protecting group. ]

A compound represented by
The following formula (2) wherein the 2- and 4-position hydroxyl groups are protected with a predetermined protecting group and the 1-position is brominated

［式中、（Ｐｒ２）は保護基を示す。］

[Wherein (Pr2) represents a protecting group. ]

After reacting with a compound represented by

A biaryl compound is produced by obtaining a biaryl compound represented by the formula:

  In the present invention, the hydroxyl group at the 2-position is protected with a predetermined protecting group, and the 5-position is boronated.

［式中、（Ｐｒ３）は保護基を示す。］

[Wherein (Pr3) represents a protecting group. ]

A compound represented by
The following formula (5) in which the hydroxyl groups at the 2-position and 4-position are protected with a predetermined protecting group and the 1-position is brominated

［式中、（Ｐｒ４）は保護基を示す。］

[Wherein (Pr4) represents a protecting group. ]

After reacting with a compound represented by

A biaryl compound is produced by obtaining a biaryl compound represented by the formula:

  In the present invention, the hydroxyl group at the 2-position is protected with a predetermined protecting group, and the 5-position is boronated.

［式中、（Ｐｒ５）は保護基を示す。］

[Wherein (Pr5) represents a protecting group. ]

A compound represented by
The following formula (8) wherein the 2- and 4-position hydroxyl groups are protected with a predetermined protecting group and the 1-position is brominated

［式中、（Ｐｒ６）は保護基を示す。］

[Wherein (Pr6) represents a protecting group. ]

And the compound represented by the following structural formula (9):

A biaryl compound is produced by obtaining a biaryl compound represented by the formula:

  According to the present invention, the hydroxyl group at the 2-position is protected with a predetermined protecting group, the compound represented by the formula (1) in which the 5-position is boronated, and the 2- and 4-position hydroxyl groups are protected with a predetermined protecting group. Then, after reacting with the compound represented by the formula (2) brominated at the 1-position, the compound is deprotected to give the following structural formula (3)

Can be synthesized. The biaryl compound represented by the structural formula (3) has an inhibitory activity against tyrosinase (hereinafter referred to as “tyrosinase inhibitory activity”), and a whitening effect can be expected.

  According to the invention, the compound represented by the formula (4) in which the hydroxyl group at the 2-position is protected with a predetermined protective group and the 5-position is boronated, and the hydroxyl groups at the 2-position and 4-position are bonded with the predetermined protective group. After protecting and reacting with the compound represented by the formula (5) brominated at the 1-position, the compound is deprotected to give the following structural formula (6)

Can be synthesized. The biaryl compound represented by the structural formula (6) has tyrosinase inhibitory activity and can be expected to have a whitening effect.

  According to the invention, the compound represented by the formula (7) in which the hydroxyl group at the 2-position is protected with a predetermined protective group and the 5-position is boronated, and the hydroxyl groups at the 2-position and 4-position are protected with the predetermined protective group. After protecting and reacting with the compound represented by the formula (8) brominated at the 1-position, the compound is deprotected to give the following structural formula (9)

Can be synthesized. The biaryl compound represented by the structural formula (9) has tyrosinase inhibitory activity and can be expected to have a whitening effect.

  The present invention provides a method for producing a biaryl compound obtained by chemical synthesis of a biaryl compound having tyrosinase inhibitory activity useful as a cosmetic material. In the method for producing a biaryl compound of the present invention, the hydroxyl group at the 2-position is protected with a predetermined protective group, the compound having a specific structure in which the 5-position is boronated, and the hydroxyl groups at the 2- and 4-positions are protected with the predetermined protective group. After reacting with a compound having a specific structure brominated at the 1-position, deprotection is performed, and biaryl compounds 1, 2, and 3 having the specific structure are obtained by chemical synthesis.

Hereinafter, details of the present invention will be described based on examples.
Example 1
<Production of Biaryl Compound 1>
In this example, 3- (2,4-dihydroxy-6-methylbenzyl) -6-hydroxy-2-methoxy-4-methylbenzoic acid (3) which is a biaryl compound 1 represented by the following structural formula (I) -(2,4-dihydroxy-6-methylbenzyl) -6-hydroxy-2-methoxy-4-methylbenzoic acid
) Obtained by chemical synthesis. Here, the following structural formula (I) corresponds to the structural formula (3).

  The synthesis of biaryl compound 1 consists of three steps. In step 1, intermediates 1 and 2 are generated from raw material compound 1, and intermediate 3 is generated from intermediate 2. In Step 2, intermediates 4 and 5 are generated from raw material compound 2, and intermediate 6 is further generated from intermediate 5. In step 3, intermediate 7 is generated from intermediate 3, and the obtained intermediate 7 and intermediate 6 are reacted to generate intermediate 8. And the intermediate bodies 9 and 10 are produced | generated from the obtained intermediate body 8, and also the biaryl compound 1 which is a final product from the intermediate body 10 is produced | generated.

[Step 1]
(Synthesis of Intermediate 1)
Raw material compound 1 represented by the following structural formula (II) (Methyl-2,6-dihydroxy-4-methyl-
Protecting the 2-position hydroxyl group of benzoate) with a protecting group gives Intermediate 1.

The protecting group for the hydroxyl group at the 2-position of the raw material compound 1 is a group having a large steric structure so that the hydroxyl group at the 2-position can be protected and bromine can be selectively introduced at the 5-position in the intermediate 3 described later. There must be. Examples of such protecting groups include tert-butyldimethylsilyl, tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl (tert -butyldiphenylsilyl) group, diethylisopropylsilyl group, dimethylisopropylsilyl (
dimethylisopropylsilyl) group, dimethylphenylsilyl group,
Diphenylisopropylsilyl group, di-tert-butylmethylsilyl group, methyldiisopropylsilyl (
methyldiisopropylsilyl) group, methyldiphenylsilyl group,
tert-butylphenylsilyl (tert-butylphenylsilyl) group, tert-butylmethoxyphenylsilyl (tert-butylmethoxyphenylsilyl) group, texyldimethylsilyl (
thexyldimethylsilyl) group.

In this example, among the above protecting groups, tert-butyldimethylsilyl (tert-
By protecting the 2-position hydroxyl group of the starting compound 1 with a butyldimethylsilyl) group (abbreviation: TBS group), an intermediate 1 (Methyl-2-tert-butyldimethylsilyl-6-hydroxy-4-methylbenzoate) is obtained. The reaction formula (III) is shown below.

  The reaction shown in the reaction formula (III) was performed under an argon atmosphere. 720 mg (18 mmol) of 60% NaH (sodium hydride) was suspended in anhydrous THF (tetrahydrofuran), and a solution obtained by dissolving 1.093 g (6 mmol) of the raw material compound 1 in anhydrous THF was added dropwise at 0 ° C. Thereafter, the mixture was stirred for 30 minutes, and a solution obtained by dissolving 1.085 g (7.2 mmol) of tert-butyldimethylsilyl chloride (abbreviation: TBS-Cl) in anhydrous THF was slowly added dropwise at 0 ° C. did. Then, it stirred at room temperature (about 20-30 degreeC) overnight and made it react.

  In addition, it was confirmed by thin layer chromatography (developing solvent; hexane: ethyl acetate = 5: 1) that intermediate 1 (Methyl-2-tert-butyldimethylsilyl-6-hydroxy-4-methylbenzoate) was produced. .

(Synthesis of Intermediate 2)
Intermediate 2 is obtained using the hydroxyl group at the 6-position of intermediate 1 synthesized as described above as the methoxy group. The reaction formula (IV) is shown below.

The reaction shown in Reaction Formula (IV) was performed under an argon atmosphere. 740 μl (12 mmol) of methyl iodide (CH ₃ I) was added dropwise to the reaction solution in which the intermediate 1 was produced as described above, and the mixture was refluxed at 20 to 80 ° C. (40 ° C. in this example) for 2 hours. After completion of the reaction, water and ethyl acetate were added to the reaction solution for phase separation, and the collected ethyl acetate phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, the filtrate was concentrated under reduced pressure, purified using silica gel column chromatography (developing solvent; hexane: ethyl acetate = 9: 1), and 297.9 g (0.96 mmol) of Intermediate 2 (Methyl-2-tert-butyldimethylsilyl-6-
methoxy-4-methylbenzoate) was obtained. At this time, in the reaction represented by the reaction formula (IV), the yield of generating the intermediate 2 from the intermediate 1 was 16%.

(Synthesis of Intermediate 3)
Bromine is introduced into the 5-position of intermediate 2 synthesized as described above to obtain intermediate 3. The reaction formula (V) is shown below.

The reaction shown in the reaction formula (V) was performed in air. First, N-bromosuccinimide (N-
Bromosuccinimide (abbreviation: NBS) 170.9 mg (0.96 mmol) and iron chloride (III) (FeCl ₃ ) 15.6 mg (0.096 mmol) were dissolved in anhydrous acetonitrile. And 297.9 mg (0.96 mmol) of the intermediate body 2 was added to this solution, and it was made to react at room temperature (about 20-30 degreeC) for 20 minutes.

At this time, it is important that NBS and FeCl ₃ are dissolved in anhydrous acetonitrile, and then intermediate 2 is added and reacted. That is, for example, even when Intermediate 2 is added to a solution of NBS dissolved in anhydrous acetonitrile and then FeCl ₃ is added, the reaction does not proceed at all.

After completion of the reaction, water and ethyl acetate were added to the reaction solution for phase separation, and the recovered ethyl acetate phase was dried over anhydrous magnesium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 9: 1) to give 33.4 mg (0.086 mmol) of intermediate 3 (Methyl -2-tert-butyldimethylsilyl-
5-bromo-6-methoxy-4-methylbenzoate) was obtained. At this time, in the reaction represented by the reaction formula (V), the yield of producing the intermediate 3 from the intermediate 2 was 9%.

The resulting intermediate 3 was measured MS and ¹ H-NMR spectrum. The spectral data of Intermediate 3 is shown in Table 1.

  Generally, the tert-butyl group of the TBS group is easily ionized. For this reason, in MS data, an ion peak with a molecular weight of 57 (tert-butyl group) less is detected from MS. Therefore, the molecular ion peak is extremely small or not detected. The addition position of bromine was confirmed by amplification of a 2.37 ppm methyl group signal when 6.66 ppm (hydrogen derived from a benzene ring) was irradiated with NOE.

[Step 2]
(Synthesis of Intermediate 4)
Intermediate 2 is obtained by protecting the 2- and 4-position hydroxyl groups of starting compound 2 (2,4-dihydroxy-6-methylbenzaldehyde) represented by the following structural formula (VI) with a protecting group.

Examples of the protecting groups for the 2-position and 4-position hydroxyl groups of the raw material compound 2 include a methylmethylether group, a tert-butoxycarbonyl group, a 2-methoxyethoxymethyl group, tert-butyl (
tert-butyl group, methylthiomethyl group, tert-butyldimethylsilyl group, trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, tert-butyldiphenyl group Silyl (tert-butyldiphenylsilyl) group, diethylisopropylsilyl (diethylisopropylsilyl) group, dimethylisopropylsilyl (
dimethylisopropylsilyl) group, dimethylphenylsilyl group, diphenylisopropylsilyl group, di-tert-butylmethylsilyl group, methyldiisopropylsilyl (
methyldiisopropylsilyl) group, methyldiphenylsilyl group, tert-butylphenylsilyl group, tert-butylmethoxyphenylsilyl group, texyldimethylsilyl (
thexyldimethylsilyl) group.

In this example, among the above protecting groups, a methylmethylether group (abbreviation: MOM group) is used to protect the hydroxyl groups at the 2-position and 4-position of the raw material compound 2 to produce intermediate 4 (
2,4-dimethoxymethyl-6-methylbenzaldehyde) is obtained. The reaction formula (VII) is shown below.

  The reaction shown in the reaction formula (VII) was performed under an argon atmosphere. 948 mg (39.5 mmol) of 60% NaH (sodium halide) and 2.0029 g (13.2 mmol) of the raw material compound 2 were suspended in anhydrous THF and stirred at 0 ° C. for 5 minutes. Thereafter, 3.0 ml (39.5 mmol) of chloromethylmethylether (abbreviation: MOM-Cl) was dropped into the mixed solution, and the mixture was stirred overnight at 25 to 80 ° C. (65 ° C. in this example). After completion of the reaction, water and ethyl acetate were added to the reaction solution for phase separation, and the recovered ethyl acetate phase was washed with saturated brine and dried over anhydrous magnesium sulfate. The solution was filtered, the filtrate was concentrated under reduced pressure, purified using silica gel column chromatography (developing solvent; hexane: ethyl acetate = 9: 1), and 2.3 g (9.6 mmol) of intermediate 4 (2,4-dimethoxymethyl-6-methylbenzaldehyde) was obtained. At this time, in the reaction represented by the reaction formula (VII), the yield of generating the intermediate 4 from the raw material compound 2 was 73%.

(Synthesis of Intermediate 5)
Intermediate 5 is obtained using the aldehyde group of intermediate 4 synthesized as described above as a hydroxyl group. Here, since the intermediate 4 is an aldehyde, it is easily oxidized to a carboxylic acid. For this reason, the reaction for obtaining the intermediate 5 must proceed immediately after the reaction for obtaining the intermediate 4 is completed. The reaction formula (VIII) is shown below.

The reaction shown in the reaction formula (VIII) was carried out in air. 723 mg (19.1 mmol) of sodium borohydride (NaBH ₄ ) was dissolved in methanol, and a solution of 2.3 g (9.6 mmol) of intermediate 4 in methanol was added dropwise thereto and stirred for 30 minutes. Thereafter, water and chloroform were added to the reaction solution for phase separation, and the recovered chloroform phase was dried over anhydrous magnesium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.7 g (7.0 mmol) of intermediate 5 (2,4-dimethoxymethyl-6-methylbenzylalcohol). At this time, in the reaction represented by the reaction formula (VIII), the yield of generating the intermediate 5 from the intermediate 4 was 73%.

(Synthesis of Intermediate 6)
Intermediate 6 is obtained by brominating the hydroxyl group of intermediate 5 synthesized as described above. The reaction formula (IX) is shown below.

The reaction shown in the reaction formula (IX) was performed in an argon atmosphere. 107 mg (0.6 mmol) of N-bromosuccinimide (abbreviation: NBS) and 53 ml (0.5 mmol) of dimethyl sulfide ((CH ₃ ) ₂ S) were dissolved in anhydrous dichloromethane at 0 ° C. Stir for 10 minutes. The reaction solution was brought to less than 0 ° C. (−20 ° C. in this example), 97 mg (0.4 mmol) of Intermediate 5 was added, and then stirred at 0 ° C. for 2 hours. Then, water and dichloromethane were added to the reaction solution for phase separation, and the recovered dichloromethane phase was washed with a sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solution was filtered, the filtrate was concentrated under reduced pressure, and purified using column chromatography (developing solvent; hexane: ethyl acetate = 9: 1) packed with activated alumina to obtain 36 mg (0.12 mmol). Intermediate 6 (
2,4-Dimethoxymethyl-6-methylbenzyl-bromide) was obtained. At this time, in the reaction represented by the reaction formula (IX), the yield of generating the intermediate 6 from the intermediate 5 was 30%.

The resulting intermediate 6 was measured MS and ¹ H-NMR spectrum. The spectrum data of the intermediate 6 is shown in Table 2.

Here, it is important that the temperature at which the intermediate 5 is added to the reaction solution is less than 0 ° C. as described above. When the temperature at which the intermediate 5 is added to the reaction solution is 0 ° C. or higher, the target intermediate 6 cannot be obtained. Moreover, it is important that the reagent used for bromination is a combination of NBS and (CH ₃ ) ₂ S. For example, the reaction does not proceed with a combination of carbon tetrabromide (CBr ₄ ) and triphenylphosphine (Ph ₃ P), a combination of NBS and Ph ₃ P, or a combination of tribromophosphine (PBr ₃ ) and pyridine. Intermediate 6 cannot be obtained. Moreover, the hydroxyl group of the intermediate 5 cannot be halogenated with chlorine or iodine other than bromine. Further, the intermediate 6 is unstable, and the pale yellow oily substance is immediately changed into orange crystals. Therefore, when purifying the product intermediate 6 as described above, it is necessary to perform purification using activated alumina, and the intermediate 6 is decomposed in the silica gel column.

[Step 3]
(Synthesis of Intermediate 7)
The bromine at the 5-position of intermediate 3 is boronated to obtain intermediate 7. The reaction formula (X) is shown below.

The reaction shown in the reaction formula (X) was performed under an argon atmosphere. 2.1 mg (2.58 μmol) of PdCl ₂ (dppf) was dissolved in dimethylformamide (DMF). Instead of _{PdCl 2, PdCl 2 (PPh 3} ) 2, Pd (dba) 2, Pt (dba) 2, Pd may be used _{(PPh 3) 4.} Then, 25.3 mg (0.258 mmol) of potassium acetate (KOAc) and 24.0 mg (0.0946 mmol) of bis (pinacolate) diboron were added, and then 33.4 mg of intermediate 3 ( 0.086 mmol) was added, and the mixture was refluxed at 40 to 100 ° C. (80 ° C. in this example) for 2 hours. At this time, potassium phenoxide, triethylamine, diisopropylethylamine, or potassium carbonate may be used instead of calcium acetate.

In addition, intermediate 7 (Methyl-6- (tert-butyldimethylsiloxy) -2-methoxy-4-methyl-3- (4,4, 5,5-
It was confirmed that tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate) was produced.

In this example, as described above, bis (pinacolato) diboron was used as a reagent for boronation, but pinacolborane (4,4,5,5-Tetramethyl-1,3), which is a monomer, was used. , 2-
When dioxaborolane) is used as a boronation reagent, bromine at the 5-position of intermediate 3 cannot be boronated.

(Synthesis of Intermediate 8)
Intermediate 7 which is a compound in which the 2-position hydroxyl group is protected with a TBS group and the 5-position is boronated, and the 2-position and 4-position hydroxyl groups are protected with a MOM group and the 1-position brominated intermediate 6 Reaction is performed to obtain Intermediate 8. The reaction formula (XI) is shown below.

The reaction shown in the reaction formula (XI) was performed in an argon atmosphere. 81.4 mg (0.258 mmol) of Ba (OH) ₂ .8H ₂ O and 26.2 mg (0.086 mmol) of intermediate 6 were added to the reaction solution in which intermediate 7 was produced as described above, The mixture was refluxed at ˜120 ° C. (100 ° C. in this example) for 1 hour. The reaction mixture was filtered through celite, extracted with dichloromethane, and washed with saturated brine. The dichloromethane phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and then purified using silica gel column chromatography (developing solvent; hexane: ethyl acetate = 2: 1) to give 33.1 mg (61. 9 μmol) of intermediate 8 (
Methyl-3- (2,4-bis (methoxymethyl) -6-methylbenzyl) -6- (tert-butyldimethyl-silyloxy) -2-methoxy-4-methylbenzoate) was obtained. At this time, in the reaction represented by the reaction formula (XI), the yield of the intermediate 8 produced by reacting the intermediate 7 with the intermediate 6 was 72%.

(Synthesis of Intermediate 9)
The TBS protecting group of Intermediate 8 synthesized as described above is removed and deprotected to obtain Intermediate 9. The reaction formula (XII) is shown below.

Reaction shown to Reaction formula (XII) was performed in the air. 33.1 mg (61.9 μmol) of Intermediate 8 was dissolved in THF, and 64.7 mg (0.2476 mmol) of Bu ₄ NF was added thereto, and reacted at room temperature (about 20 to 30 ° C.) for 20 minutes. Then, ethyl acetate was added and washed with a saturated aqueous solution of sodium dihydrogen phosphate. The ethyl acetate phase was further washed with a saturated aqueous sodium dihydrogen phosphate solution and dried over anhydrous magnesium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure and purified using silica gel column chromatography (developing solvent; ethyl acetate) to obtain 17.6 mg (42.0 μmol) of intermediate 9 (Methyl-3- (2, Four-
bis (methoxymethyl) -6-methylbenzyl) -6-hydroxy-2-methoxy-4-methylbenzoate) was obtained. At this time, in the reaction represented by the reaction formula (XII), the yield of producing the intermediate 9 from the intermediate 8 was 68%.

(Synthesis of Intermediate 10)
Intermediate 10 synthesized as described above is deprotected by elimination of the MOM protecting group of intermediate 9. The reaction formula (XIII) is shown below.

The reaction shown in the reaction formula (XIII) was carried out in air. Sodium iodide (NaI) 63.0 mg (0.42 mmol) and trimethylsilyl chloride (
Trimethylsilylchrolide (abbreviation: TMS-Cl) 45.6 mg (0.42 mmol) was dissolved in acetonitrile, and 17.6 mg (42.0 μmol) of intermediate 9 was added thereto. Reacted for 1 minute. Thereafter, ethyl acetate and a saturated aqueous sodium thiosulfate solution were added, and the mixture was further stirred for 1 hour to recover the ethyl acetate phase. The ethyl acetate phase was washed with saturated aqueous sodium thiosulfate solution, water and saturated brine, and dried over anhydrous sodium sulfate. Thereafter, the filtered filtrate was concentrated under reduced pressure and purified using silica gel column chromatography (developing solvent; chloroform: methanol = 20: 1) to obtain 11.9 mg (35.7 μmol) of intermediate 10 (Methyl-3- (2,4-dihydroxy-6-methylbenzyl) -6-hydroxy-2-methoxy-4-methylbenzoate) was obtained. At this time, in the reaction represented by the reaction formula (XIII), the yield of generating the intermediate 10 from the intermediate 9 was 85%.

(Synthesis of Biaryl Compound 1)
The biaryl compound 1 represented by the structural formula (I) as the target compound is obtained from the intermediate 10 synthesized as described above. The reaction formula (XIV) is shown below.

The reaction shown in the reaction formula (XIV) was carried out in air. 11.9 mg (35.7 μmol) of Intermediate 10 was dissolved in acetonitrile, sodium hydroxide (NaOH) was added to 0.01 N, and the mixture was reacted at room temperature (about 20 to 30 ° C.) for 1 hour. Thereafter, ethyl acetate was added to the reaction solution, and the ethyl acetate phase was washed with water and purified using silica gel column chromatography (developing solvent; chloroform: methanol = 5: 1) to obtain 6.9 mg (21.7 μmol). Biaryl Compound 1 (3- (2,4-dihydroxy-
6-methylbenzyl) -6-hydroxy-2-methoxy-4-methylbenzoic acid) was obtained. At this time, in the reaction represented by the reaction formula (XIV), the yield of producing the biaryl compound 1 from the intermediate 10 was 61%.

MS and ¹ H-NMR spectrum of the obtained biaryl compound 1 were measured. The spectral data of the biaryl compound 1 is shown in Table 3.

  The tyrosinase inhibitory activity of the biaryl compound 1 produced as described above was evaluated.

[Tyrosinase inhibitory activity evaluation method]
(A) Principle Tyrosinase (EC 1.14.18.1) is a hydroxylation from amino acid tyrosine to L-DOPA (L-β- (3,4-dihydroxyphenyl) alanine), which is the initial reaction of melanin production, L -An enzyme that catalyzes the oxidation of DOPA to DOPA quinone. In this test, L-DOPA was used as a substrate, the absorbance at 475 nm, which is the absorption wavelength of the reaction product DOPAquinone, was measured, and the inhibition rate of tyrosinase activity was determined from the inhibition of DOPAquinone production.

(B) Test method Biaryl compound 1 synthesized as described above is dissolved in 20% DMSO-1 / 15M phosphate buffer (pH 6.8) at an arbitrary concentration to prepare a sample solution. 100 μL of the prepared sample solution and 400 μL of 1/15 M phosphate buffer (pH 6.8, manufactured by Yatron Co., Ltd.) are mixed, and 60 μL of tyrosinase (30 units, manufactured by SIGMA) is added thereto, and water at 37 ° C. is added. I got used to it for 20 minutes on the bus. Thereafter, 440 μL of L-DOPA (manufactured by Wako Pure Chemical Industries, Ltd.) adjusted to 2 mM was added and reacted at 37 ° C. for 5 minutes. This is designated as sample S.

  Similarly, the sample solution to which no sample solution is added (hereinafter referred to as “control C”), the sample to which tyrosinase is not added (hereinafter referred to as “sample blank SB1”), and the sample solution and tyrosinase are not added (hereinafter referred to as “control blank”). The test sample, tyrosinase and L-DOPA were all dissolved in 1 / 15M phosphate buffer (pH 6.8) and used for the test.

Using the control blank CBl as a measurement blank, the absorbance at a wavelength of 475 nm was measured for the sample S, the control C, and the control blank CBl. From the measurement results, the tyrosinase activity inhibition rate was calculated according to the following formula (A). The test was performed 3 times, and the average was expressed as 1 data. The larger the value of the tyrosinase activity inhibition rate, the higher the tyrosinase inhibitory activity.
Tyrosinase activity inhibition rate (%) = C- {S- (SBl)} / C (A)
[In the formula, symbol C represents the absorbance of control C, S represents the absorbance of sample S, and SBl represents the absorbance of sample blank SBl. ]

[Tyrosinase inhibitory activity evaluation results]
The inhibition rate of tyrosinase activity of biaryl compound 1 produced as described above was 89.9% at a treatment concentration of 50 μg / ml, and a whitening effect was expected.

(Example 2)
<Production of Biaryl Compound 2>
In this example, 4- (4-hydroxy-6-methoxy-2,3-dimethylbenzyl) -5-methylbenzene-1,3-diol (biaryl compound 2 represented by the following structural formula (XV) ( 4- (4-Hydroxy-6-methoxy-2,3-dimethylbenzyl) -5-methyl-benzene-1,3-diol) is obtained by chemical synthesis. Here, the following structural formula (XV) corresponds to the structural formula (6).

  Biaryl compound 2 can be synthesized in the same manner as biaryl compound 1 described above.

  Specifically, the reaction corresponding to Step 1 is performed using the raw material compound 3 represented by the following structural formula (XVI) instead of the raw material compound 1 described above. Step 2 is carried out in the same manner as biaryl compound 1.

  In the production of the biaryl compound 2, corresponding to Step 1 described above, the hydroxyl group at the 2-position of the raw material compound 3 is protected with a protecting group such as a TBS group, the hydroxyl group at the 6-position is a methoxy group, and bromine is added at the 5-position. Introduce. Then, bromine at the 5-position is boronated to obtain an intermediate 11 represented by the following structural formula (XVII).

  Corresponding to Step 3 described above, the intermediate 11 and the intermediate 6 produced in Step 2 described above are reacted and then deprotected to give the biaryl compound 2 represented by the structural formula (XV). (4- (4-Hydroxy-6-methoxy-2,3-dimethylbenzyl) -5-methyl-benzene-1,3-diol) can be obtained.

(Example 3)
<Production of Biaryl Compound 3>
In this example, 4- (4-hydroxy-2-methoxy-6-methylbenzyl) -5-methylbenzene-1,3-diol (4- (4)) which is a biaryl compound 3 represented by the following structural formula (XVIII) (4-Hydroxy-2-methoxy-6-methyl-benzyl) -5-methyl-benzene-1,3-diol) is obtained by chemical synthesis. Here, the following structural formula (XVIII) corresponds to the structural formula (9).

  The biaryl compound 3 can be synthesized in the same manner as the biaryl compound 1 described above.

  Specifically, the reaction corresponding to step 1 is performed using the raw material compound 4 represented by the following structural formula (XIX) instead of the raw material compound 1 described above. Step 2 is carried out in the same manner as biaryl compound 1.

  In the production of the biaryl compound 3, corresponding to Step 1 described above, the hydroxyl group at the 2-position of the raw material compound 4 is protected with a protecting group such as a TBS group, the hydroxyl group at the 6-position is a methoxy group, and bromine is added at the 5-position. Introduce. Then, the bromine at the 5-position is boronated to obtain an intermediate 12 represented by the following structural formula (XX).

  Corresponding to Step 3 described above, the intermediate 12 and the intermediate 6 produced in Step 2 described above are reacted and then deprotected to give the biaryl compound 3 represented by the structural formula (XVIII). (4- (4-Hydroxy-2-methoxy-6-methyl-benzyl) -5-methyl-benzene-1,3-diol) can be obtained.

Claims (3)

The following formula (1) in which the hydroxyl group at the 2-position is protected with a predetermined protecting group and the 5-position is boronated

[Wherein (Pr1) represents a protecting group. ]
A compound represented by
The following formula (2) wherein the 2- and 4-position hydroxyl groups are protected with a predetermined protecting group and the 1-position is brominated

[Wherein (Pr2) represents a protecting group. ]
After reacting with a compound represented by the formula, it is deprotected to give the following structural formula (3)

A method for producing a biaryl compound, comprising obtaining a biaryl compound represented by the formula: The following formula (4) in which the hydroxyl group at the 2-position is protected with a predetermined protecting group and the 5-position is boronated

[Wherein (Pr3) represents a protecting group. ]
A compound represented by
The following formula (5) in which the hydroxyl groups at the 2-position and 4-position are protected with a predetermined protecting group and the 1-position is brominated

[Wherein (Pr4) represents a protecting group. ]
After reacting with the compound represented by the formula, it is deprotected to give the following structural formula (6)

A method for producing a biaryl compound, comprising obtaining a biaryl compound represented by the formula: The following formula (7) in which the hydroxyl group at the 2-position is protected with a predetermined protective group and the 5-position is boronated

[Wherein (Pr5) represents a protecting group. ]
A compound represented by
The following formula (8) wherein the 2- and 4-position hydroxyl groups are protected with a predetermined protecting group and the 1-position is brominated

[Wherein (Pr6) represents a protecting group. ]
And the compound represented by the following structural formula (9):

A method for producing a biaryl compound, comprising obtaining a biaryl compound represented by the formula: