JP2002020362A - New biphenyl derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new biphenyl derivative effective as a steroid sulfatase inhibitor, for treating estrone diseases such as breast cancer, endometrial cancer, endometriosis or hysteromyoma. SOLUTION: This new biphenyl derivative is shown by the formula (I) [wherein, R is COOH, CONR1R2, CONR1OCH2C6H5, COR2 or C(OH)R1R2; R1 is H or a (substituted) alkyl; and R2 is a (substituted) alkyl].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to a novel biphenyl derivative. More specifically, the following formula (I) useful as a steroid sulfatase inhibitor

Embedded image (Wherein R is -COOH, -CONR ¹ R ² , -CON
R ¹ OCH ₂ C ₆ H ₅ , —COR ² or —C (OH)
R ¹ represents R ² , R ¹ represents a hydrogen atom or an alkyl group which may have a substituent, and R ² represents an alkyl group which may have a substituent. )).

2. Description of the Related Art Breast cancer, endometrial cancer, endometriosis and uterine fibroids are known as estrogen-dependent diseases, and the estrogen concentration in these tissues is reduced and the estrogen action is suppressed. Are thought to be effective in treating these diseases. Therefore, steroid sulfatase (EC 3.1.6.2) inhibitors have been attracting attention for the purpose of suppressing estrogen production.
Various studies have been made with Reed and the like.
For example, US Pat.
It has been disclosed that sulfamate derivatives such as 3-O-sulfamate (EMATE) are useful as steroid sulfatase inhibitors. In addition, WO97 /
The compound represented by the following formula (II) (CO
UMATE) are known.

Embedded image WO 97/06793 describes the following formula (III):

Embedded image It is disclosed that it is useful as a steroid sulfatase inhibitor. However, biphenyl derivatives having a steroid sulfatase inhibitory action are not known at all.

An object of the present invention is to provide a novel compound useful as a steroid sulfatase inhibitor.

As a result of various studies, the present inventors have found that the novel biphenyl derivative represented by the above formula (I) meets the above-mentioned object, and completed the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION In the above formula (I), R ¹ , ^{R 2}
Examples of the alkyl group include a methyl group, an ethyl group,
Examples thereof include linear alkyl groups such as a propyl group and an octyl group, and these alkyl groups may have a substituent as appropriate. Examples of the substituent of the substituted alkyl group include a phenyl group which may be substituted with a lower alkyl group. Examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and a t-butyl group. The substitution position is preferably the 4-position. A particularly preferred substituted alkyl group is a 4-t-butylbenzyl group. In the formula (I), stereoisomers exist, and these stereoisomers and a mixture thereof are also included in the compound of the present invention. Further, specific examples of the biphenyl derivative of the present invention include the following compounds. 4'-acetylbiphenyl-4-yl sulfamate 4 '-[2- (4-t-butylphenyl) -acetyl]
-Biphenyl-4-ylsulfamate 4 '-(n-pentanoyl) -biphenyl-4-yl
Sulfamate 4 '-(n-heptanoyl) -biphenyl-4-yl
Sulfamate 4 '-(ethylcarbamoyl) -biphenyl-4-yl sulfamate 4'-(octylcarbamoyl) -biphenyl-4-yl sulfamate 4 '-(2-phenethylcarbamoyl) -biphenyl-
4-yl sulfamate 4 '-(4-t-butylbenzylcarbamoyl) -biphenyl-4-ylsulfamate 4'-(4-t-butylphenylcarbamoyl) -biphenyl-4-ylsulfamate 4 '-(benzyloxy Carbamoyl) -biphenyl-
4-yl sulfamate 4 '-(benzylmethylcarbamoyl) -biphenyl-
4-yl sulfamate 4 '-[(4-t-butylbenzyl) methylcarbamoyl] -biphenyl-4-yl sulfamate 4'-(benzylbutylcarbamoyl) -biphenyl-
4-yl sulfamate 4 '-[(4-t-butylbenzyl) octylcarbamoyl] biphenyl-4-yl sulfamate 4'-(sulfamoyloxy) -biphenyl-4-carboxylic acid 4 '-(1RS-hydroxyethyl) -Biphenyl-4
-Yl sulfamate 4 '-[2- (4-t-butylphenyl) -1RS-hydroxyethyl] -biphenyl-4-yl sulfamate 4'-[2- (4-t-butylphenyl) -1RS-hydroxy-1 -Methylethyl] -biphenyl-4-yl sulfamate The biphenyl derivative of the present invention can be produced by any of the following methods A and B. [Method A] The compound represented by the biphenyl derivative (I) of the present invention can be produced by the following method.

Embedded image (In the formula, R is the same as described above.) The compound (I) of the present invention is prepared by converting the compound (IV) and sodium hydride in N, N-dimethylformamide at 5 to 50 ° C.
After stirring for 20 minutes to 24 hours at 0 ° C. to 30 ° C., sulfamoyl chloride is added, and the mixture is allowed to react for 0.5 to 24 hours. Sodium hydride is generally used in the amount of 1 to 1.5 equivalents based on compound (IV). Sulfamoyl chloride is usually used in an amount of 1 to 5 equivalents based on compound (IV). [Method B] Further, among the biphenyl derivatives (I) of the present invention, compounds (I ′) in which R is represented by —CH (OH) R ²
Can also be produced by the following method.

Embedded image (In the formula, Ra represents —COR ² , and R ² is the same as described above.) The compound (I ′) of the present invention is a compound (I) obtained by Method A.
Among them, those in which R is represented by -COR ² are methanol,
In a lower alcohol such as ethanol, water or a mixed solvent thereof, sodium borohydride and 0 ° C to 30 ° C
And reacting for 0.5 to 24 hours. Sodium borohydride is compound (I)
It is usually used in an amount of 1 to 5 equivalents to a). Method A, B above
The compound (I) of the present invention obtained by the method can be converted into a hydrate of the compound by recrystallization from a water-containing solvent such as a water-containing alcohol, if necessary. The optically active compound (I) of the present invention can be obtained by separating and purifying from a stereoisomer mixture of the compound (I) obtained by the above-mentioned production method according to a conventional method.

EFFECT OF THE INVENTION The compounds of the present invention can be converted from estrone sulfate (E1S) by steroid sulfatase to estrone (E
It strongly inhibits conversion to 1) (see Test Example 1 described later). Therefore, the compounds of the present invention are effective as steroid sulfatase inhibitors against estrone-dependent diseases such as breast cancer, endometrial cancer, endometriosis and uterine fibroids. Test Example 1 Measurement of Steroid Sulfatase Inhibitory Activity: (1) Test compound: compounds of Examples 2, 7, 8, and 10 (2) Test method: Measurement of steroid sulfatase inhibitory activity of a test compound was performed in the presence of the test compound. E1S to E by purified steroid sulfatase from human placenta
This was performed by measuring the extent to which the conversion to 1 was inhibited (steroid placentas from human placenta have been reported to hydrolyze both E1S and dehydroepiandrosterone sulfate). The test compound was dissolved with dimethyl sulfoxide to a concentration of 10 mM. This was added to a reaction buffer (0.1% Brij-35).
In 50 mM Tris-HCl buffer (pH 7.4) containing
Diluted to a concentration of 0 μM. Further, a dilution buffer (0.1%
Brij-35, a 50 mM Tris-HCl buffer (pH 7.4) containing 1.2% dimethyl sulfoxide was appropriately diluted to prepare a test compound solution. This test compound solution 5
100 μL of a 40 μM E1S solution prepared in a reaction buffer to 0 μL and a method such as Suzuki [Pur
ififation and Properties
of Steroid Sulfatase from
Human Placenta, Endoclino
l. Japan, 39: 93-101. (1992)]
And purified with 0.2 μg /
50 μL of steroid sulfatase solution prepared in mL
And reacted at 37 ° C. for 60 minutes. After the reaction was completed, the steroid sulfatase was inactivated by heating at 100 ° C. for 1 minute, and the supernatant obtained by centrifugation at 3,000 rpm for 5 minutes was used as a measurement sample. The inhibitory activity was determined by analyzing a measurement sample by capillary electrophoresis and evaluating the peak area of E1 generated by the reaction. That is, the peak area of a measurement sample (control measurement sample) obtained by performing the same treatment using a dilution buffer instead of the test compound solution,
The peak area when the test compound solution of each concentration was used was determined, and each inhibition% was calculated by the following formula. Further, a 50% inhibitory concentration (IC ₅₀ ) was calculated from the concentration of the test compound and the inhibition% by the probit method.

## EQU1 ## Inhibition% = (1-S / C) × 100 S: peak area of test compound measurement sample C: peak area of control measurement sample Capillary electrophoresis was performed by the following method. That is, P / ACE5010 from Beckman was used in the electrophoresis apparatus.
And a capillary having an inner diameter of 50 μm and a total length of 37 cm, and a running buffer of 20 mM γ-cyclodextrin,
Using a 10 mM borate buffer (pH 9.0) containing 0 mM sodium dodecyl sulfate, 25 kV after the sample injection,
The electrophoresis was performed for 2.5 minutes. Sample injection was performed by pressure injection for 5 seconds, and detection was performed by ultraviolet absorption at 200 nm. Before the sample injection, the capillary was washed with 0.1 N sodium hydroxide for 1 minute, and the capillary was equilibrated with an electrophoresis buffer for 1 minute. Before the analysis, 5 μL of 40 mM-γ-cyclodextrin / 0.1 M borate buffer (pH 9.0) was added to the measurement sample per 20 μL of the sample. (2) Test results The results are shown in Table 1.

[Table 1] As shown in Table 1, the compounds of the present invention inhibited the conversion of E1S to E1 by steroid sulfatase.

The present invention will be described below with reference to examples and reference examples.
The light will be described more specifically. Example 14'-acetylbiphenyl-4-yl sulfamate 1- (4'-hydroxybiphenyl-4-yl) -eta
Non (see Reference Example 1) 100 mg of N, N-dimethylphos
60% sodium hydride (oil)
G) 20 mg and stirred for 20 minutes. Further sulfa
110 mg of moyl chloride was added and stirred for 1.5 hours.
The reaction mixture was poured into ice water, extracted with ethyl acetate, and extracted four times with water.
I washed. The obtained ethyl acetate solution is dried over anhydrous sodium sulfate.
And dried under reduced pressure. The resulting residue is
Purification by chromatography (developing solution: chloroform: acetate)
Ton = 100: 16), and the obtained crystal was
Recrystallized from a mixed solvent of ethyl acetate and ethyl acetate to give 4'-acetyl
38 mg of crystals of rubiphenyl-4-yl sulfamate
I got m. p. 184.0-184.5 ° C¹ 1 H NMR (DMSO-d₆): Δ 2.60 (3
H, s), 7.38 (2H, m), 7.84 (4H,
m), 8.03 (2H, m), 8.05 (2H, s). Elemental analysis (C₁₄H₁₃NO₄S)) Calculated (%): C, 57.72; H, 4.50; N,
4.81 Analytical value (%): C, 57.61; H, 4.45; N,
4.74 Example 24 '-[2- (4-t-butylphenyl) -acetyl]
-Biphenyl-4-ylsulfamate 2- (4-t-butylphenyl) -1- (4'-hydro
Xibiphenyl-4-yl) -ethanone (See Reference Example 5)
See) 0.62 g of N, N-dimethylformamide 20 m
86 mg of 60% sodium hydride (oil-based) in the L solution
Was added and stirred for 30 minutes. Sulfamoyl chloride
0.415 g was added, and the mixture was stirred at room temperature for 2 hours. Reaction mixture
The mixture was poured into ice water, extracted with ethyl acetate, and washed four times with water.
Was. The obtained ethyl acetate solution is dried over anhydrous sodium sulfate.
After drying, the residue was dried under reduced pressure. The resulting residue is applied to a medium pressure column.
Purification by chromatography (eluent: hexane: ethyl acetate = 2:
1) Then, the obtained crystals were mixed with cyclohexane-ethyl acetate.
The crystals were recrystallized from the combined solvent to give 4 '-[2- (4-t-butylphenyl).
Enyl) -acetyl] -biphenyl-4-yl sulf
0.39 g of crystals of the halomate were obtained. m. p. 163-164 ° C¹ 1 H NMR (DMSO-d₆): Δ 1.26 (9
H, s), 4.37 (2H, s), 7.21 (2H,
m), 7.37 (4H, m), 7.84 (4H, m),
8.12 (4H, m). Example 34 '-(n-pentanoyl) -biphenyl-4-yl
Sulfamate 1- (4'-hydroxybiphenyl-4-yl) -pen
Tan-1-one (see Reference Example 6) 0.5 g of N, N-di
60% hydrogenated sodium chloride in 5 mL of methylformamide
87 mg of oil (oil) was added and stirred for 1 hour. further
570 mg of sulfamoyl chloride was added under ice-cooling, and the mixture was added at room temperature.
For 18 hours. Pour the reaction mixture into ice water and add
Extracted with chill and washed 4 times with water. Ethyl acetate solution obtained
Is dried over anhydrous magnesium sulfate and then dried under reduced pressure.
Was. The resulting residue is purified by medium pressure silica gel chromatography (solvent
Effluent: chloroform: methanol = 99: 1)
The resulting crystals were recrystallized from methanol, and 4 '-(n-pen
Tanoyl) -biphenyl-4-yl sulfamate
0.37 g of crystals was obtained. m. p. 172-174 ° C¹ 1 H NMR (DMSO-d₆): Δ 0.92 (3
H, t, J = 7 Hz), 1.38 (2H, m), 1.6
2 (2H, m), 3.05 (2H, t, J = 6 Hz),
7.40 (2H, m), 7.83 (4H, m), 8.0
5 (4H, m). Elemental analysis (C₁₇H₁₉NO₄S
T) Calculated (%): C, 61.24; H, 5.74; N,
4.20 Analytical value (%): C, 61.38; H, 5.83; N,
4.29 Example 44 '-(n-heptanoyl) -biphenyl-4-yl
Sulfamate 1- (4'-hydroxybiphenyl-4-yl) -hep
Tan-1-one (see Reference Example 7) 0.6 g of N, N-di
60% hydrogenated sodium hydroxide in 10 mL of methylformamide
102 mg of lithium (oil) was added and stirred for 1 hour. Sa
And 0.5 g of sulfamoyl chloride under ice cooling.
Stirred at warm for 20 hours. Pour the reaction mixture into ice water and add acetic acid
Extracted with ethyl and washed 4 times with water. Ethyl acetate solution obtained
The solution was dried over anhydrous magnesium sulfate and then dried under reduced pressure.
Was. The resulting residue is purified by medium pressure silica gel chromatography (solvent
Effluent: chloroform: methanol = 99: 1) and 4 '
-(N-pentanoyl) -biphenyl-4-yl sulf
0.37 g of crystals of the famate were obtained. m. p. 172-174 ° C¹ 1 H NMR (DMSO-d₆): Δ 0.87 (3
H, t, J: 7 Hz), 1.2-1.5 (6H, m),
1.62 (2H, m), 3.04 (2H, t, J = 7.
2Hz), 7.40 (2H, m), 7.84 (4H,
m), 8.07 (4H, m). Elemental analysis (C₁₉H₂₃NO₄Calculated value (%): C, 63.13; H, 6.41; N,
3.88 Analytical value (%): C, 63.38; H, 6.56; N,
3.85 Example 54 '-(ethylcarbamoyl) -biphenyl-4-yl
Sulfamate Ethyl 4'-hydroxybiphenyl-4-carboxylate
Mid (see Reference Example 8) 0.3 g of N, N-dimethylform
In a 10 mL solution of muamide, add 60% sodium hydride (oil
G) 105 mg and stirred for 30 minutes. More sulph
Add 520 mg of amoyl chloride and stir at room temperature for 17 hours.
Stirred. Pour the reaction mixture into ice water and extract with ethyl acetate
And washed 4 times with water. The obtained ethyl acetate solution is subjected to sulfuric anhydride.
After drying with magnesium, it was dried under reduced pressure. Got
The residue was recrystallized from a hexane-ethyl acetate mixed solvent,
4 '-(ethylcarbamoyl) -biphenyl-4-yl
 125 mg of crystals of the sulfamate were obtained.¹ 1 H NMR (DMSO-d₆): Δ 1.13 (3
H, t, J = 7.1 Hz), 3.29 (2H, m),
7.37 (2H, m), 7.78 (4H, m), 7.9
4 (4H, m), 8.49 (3H, t, J = 5.9H
z). Elemental analysis (C_FifteenH₁₆N₂O₄Calculated value (%): C, 56.24; H, 5.03; N,
8.74 Analytical value (%): C, 56.22; H, 5.04; N,
8.67 Example 64 '-(octylcarbamoyl) -biphenyl-4-i
Le sulfamate Octyl 4'-hydroxybiphenyl-4-carboxylate
Amide (see Reference Example 9) 0.5 g of N, N-dimethylpho
Add a 60% sodium hydride (oil
G) 70 mg and stirred for 1 hour. Further under ice cooling
Add 445 mg of Famoyl chloride and leave at room temperature for 18 hours
Stirred. Pour the reaction mixture into ice water and extract with ethyl acetate
And washed 4 times with water. The obtained ethyl acetate solution is subjected to sulfuric anhydride.
After drying with magnesium, it was dried under reduced pressure. Got
The residue is purified by medium pressure column chromatography (eluent: chloroform).
M: methanol = 95: 5) and 4 '-(octylcal
Bamoyl) -biphenyl-4-yl sulfamate
0.34 g was obtained. m. p. 212-214 ° C¹ 1 H NMR (DMSO-d₆): Δ 0.86 (3
H, t, J = 6.9 Hz), 1.27 (10H, m),
1.52 (2H, m), 3.25 (2H, t, J = 6.
9Hz), 7.40 (2H, m), 7.80 (4H,
m), 7.93 (2H, m), 8.04 (2H, s),
8.42 (1H, d, J = 5.4 Hz). Elemental analysis (C₂₁H₂₈N₂O₄Calculated value (%): C, 62.35; H, 6.98; N,
6.93 Analytical value (%): C, 62.08; H, 7.00; N,
6.89 Example 74 '-(2-phenethylcarbamoyl) -biphenyl-
4-yl sulfamate 4'-hydroxybiphenyl-4-carboxylic acid 2-fe
0.5 g of N, N-di-netylamide (see Reference Example 10)
60% hydrogenated sodium hydroxide in 10 mL of methylformamide
76 mg of lithium (oil) was added and stirred for 1 hour. further
Add 0.37 g of sulfamoyl chloride and leave for 2 hours at room temperature
While stirring. Pour the reaction mixture into ice water and extract with ethyl acetate.
Take out and wash 4 times. The obtained ethyl acetate solution is dried with anhydrous sulfur.
After drying over sodium acid, the mixture was dried under reduced pressure. Got
The residue was purified by thin-layer chromatography (developing solution: chloro
Form: acetone = 10: 1), and the obtained crystals are meta-
Recrystallized from phenol and 4 '-(2-phenethylcarbamo
Crystal of yl) -biphenyl-4-yl sulfamate
0.1 g was obtained. m. p. 250 ° C or higher¹ 1 H NMR (DMSO-d₆): Δ 2.86 (2
H, t, J = 7.9 Hz), 3.50 (2H, m),
7.1-7.4 (7H, m), 7.80 (4H, m),
7.92 (2H, m), 8.08 (2H, s), 8.6
4 (1H, m). Elemental analysis (C₂₁H₂₀N₂O₄Calculated value (%): C, 63.62; H, 5.08; N,
7.07 Analytical value (%): C, 63.96; H, 5.10; N,
6.96 Example 84 '-(4-t-butylbenzylcarbamoyl) -biph
Phenyl-4-yl sulfamate 4'-hydroxybiphenyl-4-carboxylic acid 4-t-
0.5 g of butylbenzylamide (see Reference Example 11)
60% in N, N-dimethylformamide 10 mL solution
Add 66 mg of sodium hydride (oil) and stir for 1 hour
Was. Further, 0.32 g of sulfamoyl chloride was added,
Stirred at room temperature for 2 hours. Pour the reaction mixture into ice water and add acetic acid
Extracted with ethyl and washed 4 times with water. Ethyl acetate solution obtained
The solution was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure.
Was. The obtained residue was purified by thin-layer chromatography (exhibition
Opening solution: chloroform: acetone = 10: 1)
The resulting crystals were recrystallized from ethyl acetate to give 4 '-(4-t-butyl).
Tylbenzylcarbamoyl) -biphenyl-4-yl
0.19 g of crystals of the sulfamate were obtained. m. p. 201-202 ° C¹ 1 H NMR (DMSO-d₆): Δ 1.26 (9
H, s), 4.46 (2H, d, J = 5.9 Hz),
7.25 (2H, m), 7.37 (4H, m), 7.8
0 (4H, m), 7.86 (2H, m), 8.08 (2
H, s), 9.1 (1H, m). Elemental analysis (C₂₄H₂₆N₂O₄Calculated value (%): C, 65.73; H, 5.98; N,
6.39 Analytical value (%): C, 65.73, H, 5.96; N,
6.35 Example 94 '-(4-t-butylphenylcarbamoyl) -biph
Phenyl-4-yl sulfamate 4'-hydroxybiphenyl-4-carboxylic acid 4-t-
0.5 g of butylphenylamide (see Reference Example 12)
60% in N, N-dimethylformamide 10 mL solution
Add 68 mg of sodium hydride (oil) and stir for 1.5 hours
Stirred. Further, 0.32 g of sulfamoyl chloride was added.
And stirred at room temperature for 2 hours. Pour the reaction mixture into ice water,
Extracted with ethyl acetate and washed 4 times with water. The obtained ethyl acetate
Solution is dried over anhydrous sodium sulfate and then dried under reduced pressure.
did. The residue obtained is purified by medium pressure column chromatography (elution
Liquid: hexane: ethyl acetate = 3: 1 to 2: 1)
The crystals were recovered from a mixed solvent of cyclohexane and ethyl acetate.
Crystallized, 4 '-(4-t-butylphenylcarbamoy
) -Biphenyl-4-yl sulfamate crystals
0.32 g was obtained. m. p. 169-171 ° C¹ 1 H NMR (DMSO-d₆): Δ 1.29 (9
H, s), 7.40 (4H, m), 7.71 (2H,
m), 7.86 (4H, m), 8.07 (4H, m),
10.24 (1H, s). Elemental analysis (C₂₃H₂₄N₂O₄Calculated value (%): C, 65.07; H, 5.70; N,
6.60 Analytical value (%): C, 65.16; H, 5.91; N,
6.31 Example 104 '-(benzyloxycarbamoyl) -biphenyl-
4-yl sulfamate Benzyl 4'-hydroxybiphenyl-4-carboxylate
Oxyamide (see Reference Example 13) 1.0 g of N, N-di
60% hydrogenated sodium hydroxide in 10 mL of methylformamide
138 mg of lithium (oil) was added and stirred for 1 hour. Further
Was added with 724 mg of sulfamoyl chloride under ice cooling.
Stirred for hours. The reaction mixture was poured into ice water and the precipitated crystals
Was collected by filtration and washed with water and methanol. The obtained crystal
N, N-dimethylformamide-ethanol mixed solvent
Recrystallization twice, 4 '-(benzyloxycarbamoy
) -Biphenyl-4-yl sulfamate crystal 3
4 mg were obtained. m. p. 212-214 ° C¹ 1 H NMR (DMSO-d₆): Δ 4.95 (2
H, s), 7.3-7.6 (7H, m), 7.81 (6
H, m), 8.05 (2H, s), 11.81 (1H,
s). Elemental analysis (C₂₀H₁₈N₂O₅Calculated as (S): C, 60.29; H, 4.55; N,
7.03 Analytical value (%): C, 60.56; H, 4.68; N,
6.98 Example 114 '-(benzylmethylcarbamoyl) -biphenyl-
4-yl sulfamate 4'-hydroxybiphenyl-4-carboxylic acid benzyl
0.41 g of N, N
-60% hydrogenation in 15 mL dimethylformamide solution
Add 62 mg of sodium (oil) and stir for 1.5 hours
Was. Further, add 300 mg of sulfamoyl chloride,
Stirred at room temperature for 2 hours. Pour the reaction mixture into ice water and add acetic acid
Extracted with ethyl and washed 4 times with water. Ethyl acetate solution obtained
The solution was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure.
Was. The obtained residue was purified by thin-layer chromatography (exhibition
Opening solution: chloroform: acetone = 20: 1)
The crystals were recovered from a mixed solvent of cyclohexane and ethyl acetate.
Crystallized, 4 '-(benzylmethylcarbamoyl) -biph
170 mg of crystals of enyl-4-yl sulfamate
Obtained. m. p. 189-190 ° C¹ 1 H NMR (DMSO-d₆): Δ 2.90 (3
H, s), 4.4-4.8 (2H, m), 7.1-7.
5 (7H, m), 7.54 (2H, m), 7.77 (4
H, m), 8.05 (2H, s). Elemental analysis (C₂₁H₂₀N₂O₄Calculated value (%): C, 63.62; H, 5.08; N,
7.07 Analytical value (%): C, 63.57; H, 5.12; N,
7.02 Example 124 '-[(4-t-butylbenzyl) methylcarbamoy
Ru] -biphenyl-4-yl sulfamate 4'-hydroxybiphenyl-4-carboxylic acid (4-
t-butylbenzyl) methylamide (see Reference Example 19)
 0.44 g of N, N-dimethylformamide 10 mL
To the solution, 52% of 60% sodium hydride (oil) under ice cooling
g was added and stirred for 30 minutes. Sulfamoi under ice-cooling
277 mg of luchloride was added, and the mixture was stirred at room temperature for 2 hours.
The reaction mixture was poured into ice water, extracted with ethyl acetate, and extracted four times with water.
I washed. The obtained ethyl acetate solution is dried over anhydrous sodium sulfate.
And dried under reduced pressure. The resulting residue is
Purification by chromatography (developing solution: chloroform: acetate)
Ton = 20: 1), and the obtained crystal was subjected to cyclohexane-
The crystals were recrystallized from a mixed solvent of ethyl acetate, and 4 '-[(4-t
-Butylbenzyl) methylcarbamoyl] -biphenyl
0.21 g of crystals of -4-yl sulfamate was obtained. m. p. 193-194 ° C¹ 1 H NMR (DMSO-d₆): Δ 2.63 (9
H, s), 4.23 (3H, s), 5.7-6.1 (2
H, m), 8.4-8.7 (2H, m), 8.73 (4
H, m), 8.89 (2H, m), 9.11 (4H,
m), 9.38 (2H, s). Example 134 '-(benzylbutylcarbamoyl) -biphenyl-
4-yl sulfamate 4'-hydroxybiphenyl-4-carboxylic acid benzyl
Rubutylamide (see Reference Example 21) 0.5 g of N, N-
To a 10 mL solution of dimethylformamide, add 60% hydrogenated
64 mg of thorium (oil) was added and stirred for 30 minutes.
Further, 0.32 g of sulfamoyl chloride was added,
For 2 hours. Pour the reaction mixture into ice water and add ethyl acetate.
And washed four times with water. Ethyl acetate solution obtained
After drying over anhydrous sodium sulfate, it was evaporated to dryness under reduced pressure. Profit
The obtained residue was purified by thin-layer chromatography (developing solution:
Chloroform: acetone = 20: 1) and the obtained crystals
Was recrystallized from a mixed solvent of cyclohexane and ethyl acetate.
And 4 '-(benzylbutylcarbamoyl) -biphenyl
110 mg of crystals of ru-4-yl sulfamate were obtained.
Was. m. p. 137-138 ° C¹ 1 H NMR (DMSO-d₆): Δ 0.6-1.7
(7H, m), 3.19 (2H, m), 4.4-4.8
(2H, m), 7.1-7.4 (7H, m), 7.51
(2H, m), 7.77 (4H, m), 8.03 (2
H, s). Elemental analysis (C₂₄H₂₆N₂O₄Calculated value (%): C, 65.73; H, 5.98; N,
6.39 Analytical value (%): C, 65.59; H, 6.02; N,
6.33 Example 144 '-[(4-t-butylbenzyl) octylcarbamo
Yl] -biphenyl-4-yl sulfamate 4'-hydroxybiphenyl-4-carboxylic acid 4-t-
Butylbenzyloctylamide (see Reference Example 22)
47 g of N, N-dimethylformamide 10 mL solution
, Add 48 mg of 60% sodium hydride (oil-based) to
Stirred for hours. Furthermore, sulfamoyl chloride 0.23
g was added and stirred at room temperature for 1 hour. Reaction mixture in ice water
The mixture was poured, extracted with ethyl acetate, and washed four times with water. Vinegar obtained
The ethyl acetate solution was dried over anhydrous sodium sulfate, and then dried under reduced pressure.
To dryness. The obtained residue is purified by medium pressure column chromatography.
(Eluent: hexane: ethyl acetate = 1: 1).
Crystals were reconstituted from a mixed solvent of cyclohexane and ethyl acetate.
4 '-[(4-t-butylbenzyl) octylka
Rubamoyl] -biphenyl-4-yl sulfamate
0.28 g of crystal was obtained. m. p. 114-117 ° C¹ 1 H NMR (DMSO-d₆): Δ 0.7-1.6
(24H, m), 3.1-3.4 (2H, m), 4.4
-4.8 (2H, m), 7.1-7.4 (6H, m),
7.50 (2H, m), 7.77 (4H, m), 8.0
8 (2H, s). Elemental analysis (C₃₂H₄₂N₂O₄Calculated value (%): C, 69.78; H, 7.69; N,
5.09 Analytical value (%): C, 69.90; H, 7.71; N,
4.89 Example 154 '-(sulfamoyloxy) -biphenyl-4-ca
Rubonic acid 2.0 g of 4'-hydroxybiphenyl-4-carboxylic acid
Of N, N-dimethylformamide in 60 mL
% Sodium hydride (oil-based) 0.78 g for 30 minutes
Stirred. Further, 4.8 g of sulfamoyl chloride was added.
And stirred at room temperature overnight. Pour the reaction mixture into 2 L of water
The precipitated crystals were collected by filtration and washed with water. The obtained crystal
Recrystallized from methanol, 4 '-(sulfamoyloxy
0.75 g of crystals of b) -biphenyl-4-carboxylic acid
Obtained. m. p. 250 ° C or higher¹ 1 H NMR (DMSO-d₆): Δ 7.40 (2
H, m), 7.82 (4H, m), 8.02 (4H,
m), 12.97 (1H, br). Elemental analysis (C₁₃H₁₁NO₅Calculated value (%): C, 53.24; H, 3.78; N,
4.78 Analytical value (%): C, 53.49; H, 3.91; N,
4.68 Example 164 '-(1RS-hydroxyethyl) -biphenyl-4
-Ill sulfamate 4'-acetylbiphenyl-4-yl sulfamate
(See Example 1) A solution of 0.25 g of methanol in 20 mL
16 mg of sodium borohydride
And then add 10 mg of sodium borohydride
Stir for 30 minutes. The reaction mixture was concentrated under reduced pressure. Obtained
Water was added to the residue, which was extracted with ethyl acetate. Vinegar obtained
Wash the ethyl acid solution twice with water and dry over anhydrous sodium sulfate
After that, the mixture was dried under reduced pressure. The obtained residue is subjected to thin layer chromatography.
Purified by chromatography (developing solution: chloroform: methanol)
= 50: 1), and the obtained crystals were subjected to cyclohexane-acetic acid.
Recrystallized from a mixed solvent of ethyl, and 4 '-(IRS-hydro
(Xyethyl) -biphenyl-4-yl sulfamate
90 mg of crystals were obtained. m. p. 148-149 ° C¹ 1 H NMR (DMSO-d₆): Δ 1.34 (3
H, d, J = 6.5 Hz), 4.76 (1H, m),
5.15 (IH, d, J = 4.2 Hz), 7.34 (2
H, m), 7.42 (2H, m), 7.59 (2H,
m), 7.71 (2H, m), 8.00 (2H, s). Elemental analysis (C₁₄H_FifteenNO₄Calculated value (%): C, 57.32; H, 5.15; N,
4.77 Analytical value (%): C, 57.34; H, 5.20; N,
4.77 Example 174 '-[2- (4-t-butylphenyl) -1RS-H
Droxyethyl] -biphenyl-4-yl sulfame
To 4 '-[2- (4-t-butylphenyl) -acetyl]
-Biphenyl-4-ylsulfamate (see Example 2)
See) Hydrogenated hydrogen in a solution of 0.25 g of methanol in 20 mL.
42 mg of sodium iodide was added, and the mixture was stirred at room temperature for 1 hour.
The reaction mixture was concentrated under reduced pressure, water was added to the obtained residue, and acetic acid was added.
Extracted with ethyl. Wash the obtained ethyl acetate solution twice with water
And dried over anhydrous sodium sulfate.
Was. The residue obtained is purified by medium pressure column chromatography (elution
Liquid: hexane: ethyl acetate = 3: 2), and the obtained crystals
Is recrystallized from a mixed solvent of cyclohexane-ethyl acetate,
4 '-[2- (4-t-butylphenyl) -1RS-h
Droxyethyl] -biphenyl-4-yl sulfame
There were obtained 0.16 g of crystals of a salt. m. p. Decomposed around 230 ° C¹ 1 H NMR (DMSO-d₆): Δ 1.26 (9
H, s), 2.87 (2H, m), 4.8 (1H,
m), 5.28 (IH, d, J = 4.9 Hz), 7.1
5 (2H, m), 7.27 (2H, m), 7.35 (2
H, m), 7.45 (2H, m), 7.62 (2H,
m), 7.74 (2H, m), 8.04 (2H, s). Elemental analysis (C₂₄H₂₇NO₄Calculated value (%): C, 67.74, H, 6.40; N,
3.29 Analytical value (%): C, 67.81; H, 6.51; N,
3.21 Example 18 4 '-[2- (4-t-butylphenyl) -1RS-h
Droxy-1-methyleTyl] -biphenyl-4-yl
Sulfamate 4 '-[2- (4-t-butylphenyl) -1RS-h
Droxy-1-methylethyl] -biphenyl-4-o
(See Reference Example 23) 0.5 g of N, N-dimethylform
In a 10 mL solution of muamide, add 60% sodium hydride (oil
66 mg) and stirred for 1 hour. Further sulfa
Add 0.32 g of moyl chloride and stir at room temperature for 2 hours.
Was. The reaction mixture was poured into ice water, extracted with ethyl acetate,
Washed twice. The obtained ethyl acetate solution is dried over anhydrous sodium sulfate.
And dried under reduced pressure. The resulting residue is medium
Purification by pressure column chromatography (eluent: hexane: ethyl acetate
= 2: 1 to 1: 1), and the resulting crystals are
Recrystallized from a mixed solvent of ethyl acetate and ethyl acetate to give 4 '-[2-
(4-t-butylphenyl) -1RS-hydroxy-1
-Methylethyl] -biphenyl-4-yl sulfame
30 mg of crystals were obtained. m. p. Decomposes around 158 ° C¹ 1 H NMR (DMSO-d₆): Δ 1.24 (9
H, s), 1.37 (3H, s), 2.92 (2H,
s), 5.05 (1H, s), 7.04 (2H, m),
7.20 (2H, m), 7.35 (2H, m), 7.5
8 (4H, m), 7.74 (2H, m), 8.05 (2
H, s). Elemental analysis (C₂₅H₂₉NO₄Calculated value (%): C, 68.31; H, 6.65; N,
3.19 Analytical value (%): C, 68.16; H, 6.76; N,
3.04 Reference Example 11- (4'-hydroxybiphenyl-4-yl) -eta
Non 3.4 g of 4'-hydroxybiphenyl-4-carboxylic acid
To a 7 mL solution of tetrahydrofuran under ice cooling.
90 mL of chilled lithium ether solution is added dropwise and stirred for 2 hours
Then, the mixture was further stirred at room temperature overnight. Add salt under ice cooling to the reaction mixture
Add ammonium chloride aqueous solution and adjust to pH 3 with 1N hydrochloric acid
Then, the mixture was extracted with ethyl acetate and washed twice with water. Then saturated carbonic acid
Wash with aqueous sodium hydrogen solution and then with brine, and dry over anhydrous sodium sulfate.
After drying with thorium, it was evaporated to dryness under reduced pressure. The residue obtained
Is washed with methanol to give 1- (4'-hydroxybifu
1.01 g of crystals of phenyl-4-yl) -ethanone were obtained.
Was. m. p. 210-211 ° C¹ 1 H NMR (DMSO-d₆): Δ 2.57 (3
H, s), 6.86 (2H, m), 7.58 (2H,
m), 7.72 (2H, m), 7.96 (2H, m),
9.69 (2H, s). Elemental analysis (C₁₄H₁₂O₂Calculated value (%): C, 79.22; H, 5.70 Analytical value (%): C, 79.15; H, 5.72 Reference example 24'-methoxymethoxybiphenyl-4-carboxylic acid 20 g of 4'-hydroxybiphenyl-4-carboxylic acid
N, N-dimethylformamide 300mL solution, 60
4.5% sodium hydride (oil-based) and stirred for 30 minutes
Stirred. Next, methoxymethyl chloride was added to the reaction mixture.
0 g was added and the mixture was stirred at room temperature overnight. Reaction mixture in ice water
Poured and the precipitated crystals were collected by filtration. The obtained crystals are washed with acetic acid.
Dissolved in chill and washed with water. Ethyl acetate solution obtained
After drying with sodium hydrogen sulfate, the mixture was dried under reduced pressure. Get
The residue was mixed with 150 mL of water and 300 mL of dioxane.
Dissolve in the solvent and add 60 mL of 8N aqueous sodium hydroxide
In addition, the mixture was heated and stirred at 90 ° C. for 3 hours. Vacuum the reaction mixture
Concentrate, adjust to pH 5 with 1N hydrochloric acid, extract with ethyl acetate
Was. The ethyl acetate solution obtained after filtering off insolubles was washed with water,
After drying over anhydrous sodium sulfate and drying under reduced pressure, 4'-
Methoxymethoxybiphenyl-4-carboxylic acid 19.6
g was obtained.¹ 1 H NMR (CDCl 3): δ 3.53 (3H,
s), 5.25 (2H, s), 7.16 (2H, m),
7.59 (2H, m), 7.68 (2H, m), 8.1
7 (2H, m). Reference Example 34'-methoxymethoxybiphenyl-4-carboxylic acid
Tyl (pyridin-2-yl) amide 4'-methoxymethoxybiphenyl-4-carboxylic acid
(See Reference Example 2) 3.0 g, 2- (methylamino) pyri
Gin 1.1 g, 1-hydroxybenzotriazole monohydrate
1.7 g of N, N-dimethylformamide of 1.7 g of the hydrate
To the solution was added 1-ethyl-3- (3-dimethylaminohydrochloride).
(Ropyl) 2.2 g of carbodiimide was added and the mixture was heated at 90 ° C. for 4 hours.
The mixture was heated and stirred. Pour the reaction mixture into ice water and add ethyl acetate
Extracted and washed 4 times with water. Ethyl acetate solution obtained is anhydrous
After drying over sodium sulfate, it was evaporated to dryness under reduced pressure. Obtained
The residue was purified by medium pressure column chromatography (eluent: chloropho
Lum: methanol = 100: 1) and 4'-methoxymeth
Methyl toxibiphenyl-4-carboxylate (pyridine-
2.9 g of 2-yl) amide were obtained.¹ H NMR (CDCl₃): Δ 3.51 (3H,
s), 3.62 (3H, s), 5.22 (2H, s),
6.88 (1H, m), 7.08 (3H, m), 7.4
-7.6 (7H, m), 8.48 (1H, m). Reference example 42- (4-t-butylphenyl) -1- (4'-methoxy
Cimethoxybiphenyl-4-yl) -ethanone To a suspension solution of 0.27 g of magnesium in 10 mL of ether
2.58 g of 4-t-butylbenzyl bromide in ether
5 ml of the solution is added dropwise, and at room temperature under argon atmosphere for 30 minutes
Stirred. The obtained reaction mixture is mixed with dry ice-acetone.
4'-methoxymethoxybiphenyl-
Methyl 4-carboxylate (pyridin-2-yl) amide
(See Reference Example 3) 2.9 g of tetrahydrofuran 200
The solution was added dropwise to the mL solution and stirred for 3 hours. Chloride the reaction mixture
Dilute with aqueous ammonium and extract with ethyl acetate.
The obtained ethyl acetate solution was washed twice with water and dried over anhydrous sodium sulfate.
And dried under reduced pressure. The resulting residue is medium
Purification by pressure column chromatography (eluent: hexane: ethyl acetate
= 3: 1) and 2- (4-t-butylphenyl) -1
-(4'-methoxymethoxybiphenyl-4-yl)-
0.36 g of ethanone was obtained.¹ H NMR (CDCl₃): Δ 1.32 (9H,
s), 3.53 (3H, s), 4.29 (2H, s),
5.25 (2H, s), 7.15 (2H, m), 7.2
6 (2H, m), 7.38 (2H, m), 7.62 (4
H, m), 8.09 (2H, m). Reference Example 5 2- (4-t-butylphenyl) -1- (4'-hydro
Xibiphenyl-4-iLe)-Ethanone 2- (4-t-butylphenyl) -1- (4'-methoxy)
Cimethoxybiphenyl-4-yl) -ethanone (Reference example)
4) 0.85 g in methanol 10 mL, ethyl acetate
Dissolve in 30 mL of the mixed solvent, and add 4N hydrochloric acid (ethyl acetate
3 mL) and stirred overnight at room temperature. Vinegar reaction mixture
The mixture was diluted with ethyl acid and washed twice with water. Ethyl acetate obtained
The solution was dried over anhydrous sodium sulfate and then dried under reduced pressure.
And 2- (4-t-butylphenyl) -1- (4'-h
0.78 g of droxybiphenyl-4-yl) -ethanone
I got A product obtained by recrystallizing part of methanol
Showed the following physical properties. m. p. 153-155 ° C¹ 1 H NMR (DMSO-d₆): Δ 1.26 (9
H, s), 4.33 (2H, s), 6.88 (2H,
m), 7.20 (2H, m), 7.33 (2H, m),
7.59 (2H, m), 7.74 (2H, m), 8.0
7 (2H, m), 9.74 (1H, s). Elemental analysis (C₂₄H₂₄O₂Calculated value (%): C, 83.69; H, 7.02 Analysis value (%): C, 83.31; H, 7.04 Reference example 61- (4'-hydroxybiphenyl-4-yl) -pen
Tan-1-one 4'-hydroxybiphenyl-4-carboxylic acid 5.0 g
Was added to a 200 mL solution of
1.6Mn-butyllithium hexane solution in gon atmosphere
44 mL of the liquid was added dropwise and stirred for 4 hours. In the reaction mixture,
An ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate.
The obtained ethyl acetate solution is dried over anhydrous magnesium sulfate.
After that, the mixture was dried under reduced pressure. The residue obtained is filtered with a medium pressure column.
Purification by chromatography (eluent: hexane: ethyl acetate = 5:
2) and 1- (4'-hydroxybiphenyl-4-i
2.7 g of l) -pentan-1-one were obtained.¹ H NMR (CDCl₃): Δ 0.97 (3H,
t, J = 7.3 Hz), 1.42 (2H, m), 1.7
5 (2H, m), 2.99 (2H, t, J = 7.2H
z), 5.06 (1H, s), 6.92 (2H, m),
7.52 (2H, m), 7.63 (2H, m), 8.0
0 (2H, m). Reference Example 71- (4'-hydroxybiphenyl-4-yl) -hep
Tan-1-one 4'-hydroxybiphenyl-4-carboxylic acid 5.0 g
Was added to a 200 mL solution of
25% n-hexyllithium hexane solution under gon atmosphere
35 mL of the liquid was added dropwise and stirred for 30 minutes. Reaction mixture
To the solution, and extracted with ethyl acetate
And washed with diluted hydrochloric acid and water. Ethyl acetate solution obtained
After drying over anhydrous magnesium sulfate, it was evaporated to dryness under reduced pressure.
The residue obtained is purified by medium pressure column chromatography (eluate:
Xan: ethyl acetate = 5: 1 to 5: 2) and 1- (4 '
-Hydroxybiphenyl-4-yl) -heptane-1-
1.2 g of on was obtained.¹ H NMR (CDCl₃): Δ 0.89 (3H,
m), 1.1-1.5 (6H, m), 1.78 (2H,
m), 2.99 (2H, t, J = 7.3 Hz), 5.1
(1H, br), 6.94 (2H, m), 7.51 (2
H, m), 7.62 (2H, m), 8.01 (2H,
m). Reference Example 8Ethyl 4'-hydroxybiphenyl-4-carboxylate
Mid 1.0 g of 4'-hydroxybiphenyl-4-carboxylic acid
To a 10 mL solution of dioxane in 1-hydroxybenzoto
0.67 g of riazole monohydrate, 1-ethyl-3-hydrochloric acid
(3-dimethylaminopropyl) carbodiimide 1.0
7 g was added, and the mixture was stirred at room temperature for 1 hour. More ethylami
(70% aqueous solution) at room temperature for 18 hours
Stirred. Pour the reaction mixture into ice water and extract with ethyl acetate
Then, it was washed with water and further with brine. Ethyl acetate obtained
The solution was dried over anhydrous magnesium sulfate and then dried under reduced pressure.
did. The residue obtained is purified by medium pressure column chromatography (elution
Liquid: chloroform: methanol = 10: 1)
Recrystallization from a mixed solvent of sun-hexane gives 4'-hydroxy
0.74 g of sibiphenyl-4-carboxylic acid ethylamide
I got¹ H NMR (CDCl₃): Δ 1.28 (3H, t,
J = 7.3 Hz), 3.53 (2H, m), 6.92
(1H, m), 6.95 (2H, m), 7.51 (2
H, m), 7.59 (2H, m), 7.81 (3H,
m). Reference Example 9Octyl 4'-hydroxybiphenyl-4-carboxylate
Amide 4'-hydroxybiphenyl-4-carboxylic acid 5.0 g
In a 50 mL solution of N, N-dimethylformamide
Lower 1-hydroxybenzotriazole monohydrate 1.07
g, 1-ethyl-3- (3-dimethylaminopropyl hydrochloride)
F) 5.4 g of carbodiimide was added. Octyl
Amine (3.9 g) was added, and the mixture was stirred at room temperature for 6 hours. Reaction mixture
The mixture was poured into ice water, extracted with ethyl acetate,
It was washed with an aqueous solution of lithium and further washed with water. Got
Reduce the ethyl acetate solution after drying over anhydrous magnesium sulfate.
Dry under pressure. The obtained residue is recrystallized from methanol
And 4'-hydroxybiphenyl-4-carboxylic acid octane
3.14 g of tylamide were obtained.¹ 1 H NMR (DMSO-d₆): Δ 0.86 (3
H, t, J = 6.9 Hz), 1.27 (10H, m),
1.52 (2H, m), 3.2 (2H, t, J = 6.9)
Hz), 6.86 (2H, m), 7.56 (2H,
m), 7.66 (2H, m), 7.87 (2H, m),
8.40 (IH, d, J = 5.6 Hz), 9.61 (1
H, brs). Reference example 104'-hydroxybiphenyl-4-carboxylic acid 2-fe
Netylamide 4'-hydroxybiphenyl-4-carboxylic acid 1.3
g, 2-phenethylamine 0.74 g, 1-hydroxy
Benzotriazole monohydrate 0.93 g of N, N-dimethyl
To a 30 mL solution of tilformamide was added 1-ethyl-3 hydrochloric acid.
-(3-dimethylaminopropyl) carbodiimide
17 g was added and the mixture was heated and stirred at 90 ° C. for 3 hours. Reaction mixture
Was poured into ice water, extracted with ethyl acetate, and washed four times with water. Profit
Ethyl acetate solution was dried over anhydrous sodium sulfate
Thereafter, it was dried under reduced pressure. The obtained residue is ethyl acetate-meta
And recrystallized from a mixed solvent of 4'-hydroxybiph.
Phenyl-4-carboxylic acid 2-phenethylamide 0.94
g was obtained. m. p. 217-218 ° C¹ 1 H NMR (DMSO-d₆): Δ 2.85 (2
H, t, J = 7.9 Hz), 3.50 (2H, m),
6.87 (2H, m), 7.1-7.4 (5H, m),
7.56 (2H, m), 7.66 (2H, m), 7.8
6 (2H, m), 8.58 (1H, m), 9.66 (1
H, s). Elemental analysis (C₂₁H₁₉NO₂Calculated) (%): C, 79.47, H, 6.03; N,
4.41 Analytical value (%): C, 79.56; H, 6.02; N,
4.48 Reference Example 114'-hydroxybiphenyl-4-carboxylic acid 4-t-
Butylbenzylamide 4'-hydroxybiphenyl-4-carboxylic acid 0.8
g, 4-t-butylbenzylamine 0.61 g, 1-h
0.57 g of N,
To a solution of N-dimethylformamide (30 mL) was added hydrochloric acid 1-e.
Tyl-3- (3-dimethylaminopropyl) carbodii
0.71 g of amide was added and the mixture was heated and stirred at 90 ° C. for 3 hours. Anti
The reaction mixture was poured into ice water, extracted with ethyl acetate, and washed four times with water.
did. The obtained ethyl acetate solution is dried over anhydrous sodium sulfate.
After drying, the residue was dried under reduced pressure. The obtained residue is
Purification by muchromatography (eluent: chloroform: methanol
= 100: 1) and 4'-hydroxybiphenyl-4-
1.0 g of carboxylic acid 4-t-butylbenzylamide was obtained.
Was. The product obtained by partially recrystallizing from ethyl acetate
The following physical properties were shown. m. p. 180-181 ° C¹ 1 H NMR (DMSO-d₆): Δ 1.26 (9
H, s), 4.44 (2H, d, J = 6.0 Hz),
6.87 (2H, m), 7.24 (2H, m), 7.3
5 (2H, m), 7.57 (2H, m), 7.68 (2
H, m), 7.93 (2H, m), 9.0 (1H,
m), 9.66 (1H, s). Elemental analysis (C₂₄H₂₅NO₂Calculated) (%): C, 80.19; H, 7.01; N,
3.90 Analytical value (%): C, 80.22; H, 7.00; N,
3.91 Reference Example 124'-hydroxybiphenyl-4-carboxylic acid 4-t-
Butylphenylamide 4'-hydroxybiphenyl-4-carboxylic acid 2.0
g, 4-t-butylaniline 1.4 g, 1-hydroxy
Benzotriazole monohydrate 1.71 g of N, N-dimethyl
To a 20 mL solution of tilformamide was added 1-ethyl-3 hydrochloric acid.
-(3-dimethylaminopropyl) carbodiimide2.
15 g was added and the mixture was stirred at room temperature for 3 days. Ice the reaction mixture
, Extracted with ethyl acetate and washed four times with water. Got
After drying the ethyl acetate solution over anhydrous sodium sulfate, the pressure was reduced.
Dried down. The obtained residue is purified by medium pressure column chromatography.
(Eluent: hexane: ethyl acetate = 2: 1 to 1: 1)
And 4'-hydroxybiphenyl-4-carboxylic acid 4-
2.0 g of t-butylphenylamide was obtained.¹ 1 H NMR (DMSO-d₆): Δ 1.29 (9
H, s), 6.89 (2H, m), 7.37 (2H,
m), 7.60 (2H, m), 7.73 (4H, m),
8.01 (2H, m), 9.69 (1H, s), 10.
18 (2H, s). Reference Example 134'-hydroxybiphenyl-4-carboxylic acid benzyl
Roxyamide 4'-hydroxybiphenyl-4-carboxylic acid 3.0
g, 1-hydroxybenzotriazole monohydrate 1.0
In 7 g of N, N-dimethylformamide 45 mL solution,
1-ethyl-3- (3-dimethylaminopropyl) hydrochloride
3.21 g of carbodiimide were added. In addition, benzene hydrochloride
2.46 g of ruoxyamine and 9 mL of triethylamine
The mixture was stirred overnight at room temperature. Pour the reaction mixture into ice water and add vinegar
The mixture was extracted with ethyl acetate and washed four times with water. Ethyl acetate obtained
The solution was dried over anhydrous magnesium sulfate and then dried under reduced pressure.
did. The residue obtained is washed with ether and 4'-hydro
Xybiphenyl-4-carboxylic acid benzyloxyamide
3.14 g were obtained.¹ 1 H NMR (DMSO-d6): δ 4.94 (2
H, s), 6.86 (2H, m), 7.3-7.5 (5
H, m), 7.56 (2H, m), 7.67 (2H,
m), 7.79 (2H, m), 9.64 (1H, b
r). Reference Example 14Benzyl 4'-benzyloxybiphenyl-4-cal
Boxylate 15 g of 4'-hydroxybiphenyl-4-carboxylic acid
18 mL of benzyl bromide in N, N-dimethylforma
To a 150 mL solution of amide, add 24 g of potassium carbonate and add room temperature
For 1 day. Pour the reaction mixture into 1 L of ice water and precipitate
The crystals obtained were collected by filtration. The obtained crystals are dissolved in chloroform.
Thaw, wash with water, dry over anhydrous sodium sulfate, and
To dryness. The residue obtained is washed with methanol and benzyl
 4'-benzyloxybiphenyl-4-carboxyle
18.8 g were obtained.¹ H NMR (CDCl₃): Δ 5.13 (2H,
s), 5.39 (2H, s), 7.07 (2H, m),
7.2-7.7 (10H, m), 7.60 (4H,
m), 8.12 (2H, m). Reference Example 154'-benzyloxybiphenyl-4-carbonyl
Lorido Benzyl 4'-benzyloxybiphenyl-4-cal
18.8 g of boxylate (see Reference Example 14) in 20 m of water
L, dissolved in a mixed solution of 40 mL of dioxane,
Add 50 mL of aqueous sodium chloride solution and heat at 100 ° C overnight
Stirred. The reaction mixture was concentrated under reduced pressure, and the obtained residue was washed with water.
And adjusted to pH 3 with 1N hydrochloric acid.
The crystals were collected by filtration, washed with water, and washed with acetone to obtain 15 g of crude crystals.
To 2.58 g of the obtained crude crystals, 10 mL of thionyl chloride was added.
And heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure.
Chloroform is added to the residue, and the precipitated crystals are collected by filtration.
4'-benzyloxybiphenyl-4-carbonyl
2.5 g of chloride were obtained.¹ 1 H NMR (DMSO-d₆): Δ 5.15 (2
H, s), 7.10 (2H, m), 7.2-7.6 (5
H, m), 7.7-7.8 (4H, m), 7.96 (2
H, m). Reference Example 164'-benzyloxybiphenyl-4-carboxylic acid
Ndylmethylamide 4'-benzyloxybiphenyl-4-carbonyl
1 g of chloride (see Reference Example 15) and 0.1 g of triethylamine.
To a solution of 62 g of tetrahydrofuran in 30 mL, add N-methyl
Add 0.41 g of benzylamine and stir at room temperature overnight.
Was. The reaction mixture was poured into ice water and extracted with ethyl acetate.
After washing with 1N hydrochloric acid and washing with water, the obtained ethyl acetate solution was
After drying with sodium hydrogen sulfate, the mixture was dried under reduced pressure. Get
The residue was purified by medium pressure column chromatography (eluent: chloro
Form) and 4'-benzyloxybiphenyl-4-ca
0.95 g of benzyl benzyl methylamide was obtained.¹ 1 H NMR (DMSO-d₆): Δ 2.8-3.2
(3H, m), 4.5-4.9 (2H, m), 5.13
(2H, s), 7.07 (2H, m), 7.1-7.7
(16H, m). Reference Example 174'-hydroxybiphenyl-4-carboxylic acid benzyl
Rumethylamide 4'-benzyloxybiphenyl-4-carboxylic acid
0.45 g of benzylmethylamide (see Reference Example 16)
Dissolve in a mixed solution of 50 mL of ethanol and 50 mL of dioxane
Dissolve and 10% palladium on carbon (50% water-containing) 150mg
And catalytically reduced at normal pressure overnight. Filter the reaction mixture
And concentrated under reduced pressure to give 4'-hydroxybiphenyl-4-.
0.41 g of carboxylic acid benzylmethylamide was obtained.¹ H NMR (CDCl₃): Δ2.8-3.2 (3
H, m), 4.5-4.9 (2H, m), 6.85 (2
H, m), 7.1-7.7 (12H, m). Reference Example 184'-benzyloxybiphenyl-4-carboxylic acid
(4-t-butylbenzyl) methylamide 4'-benzyloxybiphenyl-4-carbonyl
1.2 g of chloride (see Reference Example 15), triethylamine
0.41 g of a 30 mL solution of tetrahydrofuran was added with (4
-Tert-butylbenzyl) methylamine 0.72 g of tet
A 10 mL solution of lahydrofuran was added dropwise and stirred at room temperature for 3 hours.
Stirred. Pour the reaction mixture into ice water and extract with ethyl acetate.
Was. After washing with 1N hydrochloric acid, the obtained ethyl acetate solution was dried.
After drying over sodium sulfate, it was evaporated to dryness under reduced pressure. Obtained
The residue was purified by medium pressure column chromatography (eluent: chloropho
Lum) and 4'-benzyloxybiphenyl-4-cal
Boronic acid (4-t-butylbenzyl) methylamide
2 g were obtained.¹ H NMR (CDCl₃): Δ 1.34 (9H,
s), 2.8-3.2 (3H, m), 4.4-4.8.
(2H, m), 5.12 (2H, s), 7.05 (2
H, m), 7.1-7.6 (15H, m). Reference Example 194′-hydroxybiphenyl-4-carboxylic acid (4-
t-butylbenzyl) methylamide 4'-benzyloxybiphenyl-4-carboxylic acid
(4-t-butylbenzyl) methylamide (Reference Example 18
0.6 g of methanol 50 mL, dioxane 50
dissolved in 10 mL palladium on carbon
mg, and the mixture was catalytically reduced at normal pressure for 5 hours. Reaction mixture
And concentrated under reduced pressure to give 4'-hydroxybiphenyl.
-4-Carboxylic acid (4-t-butylbenzyl) methyl
0.45 g of the amide was obtained.¹ 1 H NMR (DMSO-d₆): Δ 1.32 (9
H, s), 2.8-3.2 (3H, m), 4.4-4.
8 (2H, m), 6.82 (2H, m), 7.0-7.
4 (3H, m), 7.38 (4H, m), 7.48 (4
H, m). Reference Example 204'-benzyloxybiphenyl-4-carboxylic acid
N-butyramide 4'-benzyloxybiphenyl-4-carbonyl
1 g of chloride (see Reference Example 15) and 0.1 g of triethylamine.
To a suspension of 62 g of tetrahydrofuran in 30 mL was added N-
Add 0.56 g of butylbenzylamine and stir at room temperature for 2 hours.
Stirred. Pour the reaction mixture into ice water and extract with ethyl acetate.
Was. After washing with 1N hydrochloric acid and washing with water, the obtained ethyl acetate solution
Was dried over anhydrous sodium sulfate and then dried under reduced pressure.
The resulting residue is purified by medium pressure column chromatography (eluent:
Roloform) and 4'-benzyloxybiphenyl-4
-1.02 g of carboxylic acid benzylbutyramide was obtained.
Was.¹ H NMR (CDCl₃): Δ 0.6-1.8 (7
H, m), 3.1-3.6 (2H, m), 4.5-4.
9 (2H, m), 5.14 (2H, s), 7.07 (2
H, m), 7.1-7.7 (16H, m). Reference Example 214'-hydroxybiphenyl-4-carboxylic acid benzyl
Rubutylamide 4'-benzyloxybiphenyl-4-carboxylic acid
0.6 g of benzylbutyramide (see Reference Example 20)
Dissolved in a mixed solution of 30 mL of phenol and 30 mL of dioxane
And add 0.15 g of 10% palladium on carbon,
The reaction was reduced overnight. The reaction mixture was filtered and concentrated under reduced pressure.
And 4'-hydroxybiphenyl-4-carboxylic acid
0.5 g of benzylbutyramide was obtained.¹ 1 H NMR (DMSO-d₆): Δ 0.6-1.7
(7H, m), 3.22 (2H, m), 4.4-4.8
(2H, m), 6.85 (2H, m), 7.1-7.5
(7H, m), 7.53 (2H, m), 7.64 (2
H, m), 9.61 (1H, s). Reference Example 224'-hydroxybiphenyl-4-carboxylic acid 4-t-
Butylbenzyloctylamide 4'-hydroxybiphenyl-4-carboxylic acid 1.5
g, 4-t-butylbenzyloctylamine, 1.9 g,
1.07 g of 1-hydroxybenzotriazole monohydrate
To a solution of N, N-dimethylformamide in 20 mL
1-ethyl-3- (3-dimethylaminopropyl) cal
Add 1.34 g of bodimide and heat and stir at 60 ° C overnight.
Was. The reaction mixture was poured into ice water, extracted with ethyl acetate,
Washed twice. The obtained ethyl acetate solution is dried over anhydrous sodium sulfate.
And dried under reduced pressure. The resulting residue is medium
Purification by pressure column chromatography (eluent: chloroform: meta)
Nol = 100: 1) and 4'-hydroxybiphenyl
4-Carboxylic acid 4-t-butylbenzyloctylamido
0.47 g was obtained.¹ 1 H NMR (DMSO-d₆): Δ 0.6-1.7
(24H, m), 3.0-3.4 (2H, m), 4.4
-4.8 (2H, m), 6.85 (2H, m), 7.0
-7.5 (6H, m), 7.52 (2H, m), 7.6
3 (2H, m), 9.63 (1H, s). Reference Example 234 '-[2- (4-t-butylphenyl) -1RS-H
Droxy-1-methylethyl] -biphenyl-4-o
Le Magnesium 0.68mg suspension in ether 30mL
7.2 g of 4-t-butylbenzyl bromide in ether
10 ml of the solution was added dropwise, and at room temperature for 30 minutes under an argon atmosphere
While stirring. Further, ice-cooled 1- (4'-hydroxybiphenyl)
2.1 g of tetrahydrofura
100 ml solution was added dropwise and stirred for 2 hours. Reaction mixing
Diluted with aqueous ammonium chloride solution and extracted with ethyl acetate.
Exited and washed twice with water. The obtained ethyl acetate solution is subjected to sulfuric anhydride.
After drying over magnesium, the mixture was evaporated to dryness under reduced pressure.
The residue is washed with hexane, recrystallized from methanol,
4 '-[2- (4-t-butylphenyl) -1RS-h
Droxy-1-methylethyl] -biphenyl-4-o
1.7 g of crystallized crystals were obtained. m. p. Decomposes around 158 ° C¹ 1 H NMR (DMSO-d₆): Δ 1.23 (9
H, s), 1.35 (3H, s), 2.92 (2H,
s), 4.99 (1H, s), 6.83 (2H, m),
7.02 (2H, m), 7.19 (2H, m), 7.4
7 (6H, m), 9.51 (1H, s). Elemental analysis (C₂₅H₂₈O₂Calculated value (%): C, 83.29; H, 7.83 Analytical value (%): C, 82.87; H, 7.99

Continuation of the front page F term (reference) 4C206 AA02 AA03 CA12 JA11 NA14 ZA81 ZC11 4H006 AA01 AB20 AB27 AB28

Claims (3)

[Claims] 1. A compound represented by the following formula (I): (Wherein R is -COOH, -CONR ¹ R ² , -CON
R ¹ OCH ₂ C ₆ H ₅ , —COR ² or —C (OH)
R ¹ represents R ² , R ¹ represents a hydrogen atom or an alkyl group which may have a substituent, and R ² represents an alkyl group which may have a substituent. ). 2. R is -CONR ¹ R ² or -COR ²
The biphenyl derivative according to claim 1, which is 3. The biphenyl derivative according to claim 2, wherein R ² is a 4-t-butylbenzyl group.