JP2003104957A - Biphenylethylamine derivative and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new production intermediate for a 5-amidino-2- hydroxybenzenesulfonamide derivative useful as an activated coagulation factor X inhibitor and to provide a method for producing the intermediate. SOLUTION: This compound is represented by general formula (I) (R<1> and R<2> are each hydrogen, a halogen, a lower alkyl, a lower alkylthio or a lower alkylsulfonyl; R<3> is a halogen, a lower alkylthio or a lower alkyl sulfonyl group; R<4> is carboxy, carbamoyl or an aminomethyl group). This method for producing the compound represented by general formula (I) from a compound of formula (II) (R<1> , R<2> and R<3> as shown above) is provided.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a compound of formula (VIII) useful as an activated blood coagulation factor X inhibitor.

[Chemical 10] The present invention relates to a novel intermediate for producing a 5-amidino-2-hydroxybenzenesulfonamide derivative represented by or a pharmacologically acceptable salt thereof, and a production method thereof.

[0002]

2. Description of the Related Art The 5-amidino-2-hydroxybenzenesulfonamide derivative represented by the above formula (VIII) is a novel compound found by the applicant and not described in the literature. The benzenesulfonamide derivative (VII
As the production method of I), as shown in the following scheme in Japanese Patent Application No. 2000-305569, a compound represented by the formula (IX) is converted into a sulfonamide derivative represented by the formula (XII) as a starting material, The sulfonamide derivative (X
II) via the compound represented by formula (XIII),
A method of inducing an activated blood coagulation factor X inhibitor (VIII) is disclosed. However, there is no description about the synthetic method via the compound of the present invention.

[Chemical 11] (In the formula, R ¹ , R ² and R ³ are as defined above, R ⁵ is hydrogen or lower alkyl, and Z is hydrogen or hydroxy.)

[0003]

The object of the present invention is to provide a compound of the above formula (VII) which is useful as an activated blood coagulation factor X inhibitor.
By providing a novel intermediate capable of easily producing a 5-amidino-2-hydroxybenzenesulfonamide derivative represented by I) or a pharmacologically acceptable salt thereof in a high yield, and a production method thereof. is there.

[0004]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that 3-phenyl-2-cyclohexenone represented by the above formula (VI) is a simple starting material. It has also been found that the biphenylethylamine derivative represented by the formula (I) can be synthesized in high yield. Further, by passing through the biphenylethylamine derivative (I), the number of steps extremely shorter than that of the starting material,
Moreover, they have found that the 5-amidino-2-hydroxybenzenesulfonamide derivative represented by the formula (VIII) or a pharmacologically acceptable salt thereof can be produced in good yield, and completed the present invention.

That is, the present invention has the formula (I)

[Chemical 12] (In the formula, R ¹ and R ² are groups independently selected from the group consisting of hydrogen atom, halogen atom, lower alkyl, lower alkylthio and lower alkylsulfonyl;
³ is a halogen atom, a lower alkyl, a lower alkylthio or a lower alkylsulfonyl group).

In another aspect, the present invention provides a compound of formula (II)

[Chemical 13] (In the formula, R ¹ and R ² are groups independently selected from the group consisting of hydrogen atom, halogen atom, lower alkyl, lower alkylthio and lower alkylsulfonyl;
³ is a halogen atom, a lower alkyl, a lower alkylthio or a lower alkylsulfonyl group) and a compound represented by the formula (III)

[Chemical 14] (Wherein R ¹ , R ² and R ³ are as defined above)
A compound represented by formula (I) is prepared by reacting the compound represented by formula (III) with ammonia.
V)

[Chemical 15] (Wherein R ¹ , R ² and R ³ are as defined above)
A compound represented by formula (I), which is characterized in that the compound represented by formula (IV) is subsequently reduced.

[Chemical 16] (Wherein R ¹ , R ² and R ³ are as defined above)
Relates to a method for producing a compound represented by:

In yet another aspect, the present invention provides a compound of formula (V)

[Chemical 17] (In the formula, R ¹ and R ² are groups independently selected from the group consisting of hydrogen atom, halogen atom, lower alkyl, lower alkylthio and lower alkylsulfonyl;
³ is a halogen atom, a lower alkyl, a lower alkylthio or a lower alkylsulfonyl group, and R ⁴ is a carboxyl group or a carbamoyl group).

In yet another aspect, the present invention provides
Formula (VI)

[Chemical 18] (In the formula, R ¹ and R ² are groups independently selected from the group consisting of hydrogen atom, halogen atom, lower alkyl, lower alkylthio and lower alkylsulfonyl;
³ is a halogen atom, a lower alkyl, a lower alkylthio or a lower alkylsulfonyl group) and a compound of the formula (VII)

[Chemical 19] A compound represented by the formula (V):

[Chemical 20] (Wherein R ¹ , R ² and R ³ are as defined above, and R ⁴ is a carboxyl group).

In the present invention, the halogen atom means a fluorine atom or a chlorine atom, preferably a fluorine atom. The lower alkyl means a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl and tert-butyl. Lower alkylthio means a linear or branched alkylthio group having 1 to 6 carbon atoms, for example,
Methylthio, ethylthio, propylthio, isopropylthio and the like can be mentioned. What is lower alkylsulfonyl?
It means a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms, and examples thereof include methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl and the like.

The present invention will be described in detail below. The compounds of the present invention can be prepared according to scheme 1 below.

[Chemical 21] (In the formula, R ¹ , R ² and R ³ are as defined above.)

(Step a) 3-represented by the above formula (VI)
A phenyl-2-cyclohexenone derivative is reacted with glyoxylic acid (VII) in a solvent in the presence or absence of an acid to produce a biphenylacetic acid derivative represented by the above formula (II) of the present invention. be able to.

Examples of the solvent that can be used in this reaction include tetrahydrofuran, 1,2-dimethoxyethane,
Ethers such as dioxane, acetonitrile, N, N
-Dimethylformamide and the like can be mentioned, and these inert solvents can be used alone or in admixture of two or more, and water can be added if necessary. As the acid, concentrated sulfuric acid, concentrated hydrochloric acid, p-toluenesulfonic acid, trifluoroacetic acid, acetic acid or the like is used. This reaction is usually
The reaction can be carried out at 0 ° C to the reflux temperature of the solvent used for 1 to 24 hours, and after completion of the reaction, the desired biphenylacetic acid derivative represented by the above formula (II) can be obtained by extraction and concentration. it can.

(Step b) Next, the biphenylacetic acid derivative (I
I) is converted into a lactone derivative represented by the formula (III) by reacting I) in an inert solvent or in the absence of a solvent in the presence of a condensing agent, and then the lactone derivative (II
By reacting I) with aqueous ammonia, the biphenylacetic acid amide derivative represented by the above formula (IV) of the present invention can be produced.

As an inert solvent which can be used in this reaction,
Examples thereof include tetrahydrofuran, 1,2-dimethoxyethane, ethers such as dioxane, acetonitrile and the like, and these inert solvents can be used alone or in combination of two or more kinds. As the condensing agent, for example, acetic anhydride or the like can be used, and it is usually used by appropriately selecting from the range of 1 to 6 equivalents with respect to the biphenylacetic acid derivative (II). The conversion of the biphenylacetic acid derivative (II) to the lactone derivative (III) is usually performed at a temperature of 0 to 60 ° C for 1 to 6 hours. After completion of the reaction, the lactone derivative (III) may or may not be isolated, and preferably after confirming the production of the lactone derivative (III), the lactone derivative (III) is reacted with ammonia water without isolation to obtain a biphenylacetic acid amide derivative (IV). ) Is performed. The conversion of the lactone derivative (III) to the biphenylacetic acid amide derivative (IV) is usually 0 to
The reaction is carried out at a temperature of 50 ° C. for 1 to 6 hours, and after completion of the reaction, the compound of the above formula (I
The biphenylacetic acid amide derivative represented by V) can be obtained.

(Step c) Subsequently, the biphenylacetic acid amide derivative (IV) is reduced with a reducing agent in an inert solvent to produce the biphenylethylamine derivative represented by the above formula (I) of the present invention. be able to.

As an inert solvent which can be used in this reaction,
Examples thereof include tetrahydrofuran and 1,2-dimethoxyethane, and these inert solvents can be used alone or in combination of two or more. Examples of the reducing agent include diborane, borane / tetrahydrofuran complex, borane / dimethylsulfide complex, borane / pyridine complex, borane / N, N-diethylaniline complex, sodium borohydride / trifluoroacetic acid, sodium borohydride / acetic acid. Etc. can be used, and they are usually used by appropriately selecting from the range of 1 to 5 equivalents in terms of boron with respect to the biphenylacetic acid amide derivative (IV). This reaction is usually performed at 0 ° C to the reflux temperature of the solvent used for 1 to 1
The reaction is carried out for 2 hours, and after the completion of the reaction, an excess reducing agent is treated, if necessary, and then the desired biphenylethylamine derivative represented by the formula (I) can be obtained by extraction and concentration according to a conventional method. it can.

The thus obtained compound represented by the above formula (I) can be used as an activated blood coagulation factor X inhibitor, for example, by performing the reactions of steps d to g shown in the following scheme 2. 5 represented by the above formula (VIII), which is useful as
It can lead to an amidino-2-hydroxybenzenesulfonamide derivative.

[0018]

[Chemical formula 22] (Wherein R ¹ , R ² and R ³ are as defined above,
R ⁶ is lower alkyl, R ⁵ is hydrogen or lower alkyl, X is chloro or bromo, Z is hydrogen or hydroxy)

(Step d) The biphenylethylamine derivative represented by the formula (I) and the benzenesulfonyl chloride represented by the formula (XI) are mixed with an inert solvent (for example,
Tetrahydrofuran, N, N-dimethylformamide, etc.), in the presence of a base (eg, triethylamine, potassium carbonate, etc.), usually at a temperature of −40 to 50 ° C. to obtain a compound represented by the above formula (XIII). A sulfonamide derivative can be obtained.

(Step e) Next, sulfonamide (XII
I) and a haloacetic acid ester (XIV) in an inert solvent (eg, N, N-dimethylformamide) in the presence of a base (eg, potassium carbonate, N, N-diisopropylethylamine), usually, By reacting at 0 ° C to the reflux temperature of the solvent used, the above formula (X
It is possible to induce the compound represented by V).

(Step f) Next, the compound (XV) and lithium chloride are used in an inert solvent (eg, N, N-dimethylformamide, N, N-dimethylacetamide, etc.), usually at 100 ° C. to a solvent used. The phenol derivative represented by the formula (XVI) can be obtained by reacting at the reflux temperature of.

(Step g) Subsequently, a phenol derivative (XV
I) is reacted with a lower alcohol (eg, ethanol) in the presence of hydrogen halide and then with ammonia or a salt thereof or hydroxylamine or a salt thereof, and if necessary, an ester group according to a conventional method. Is hydrolyzed or is subjected to transesterification using an alcohol represented by R ⁵ OH to produce a compound represented by the above formula (VIII), which is useful as a pharmaceutical. If desired, the compound (VIII) can be converted into its pharmaceutically acceptable salt according to a conventional method.

The compound represented by the above formula (VI), which is the starting material shown in Scheme 1 above, can be produced, for example, as shown below.

[Chemical formula 23] (In the formula, R ⁷ is lower alkyl, and R ¹¹ , R ¹² , R ¹³
Are independently hydrogen, halogen, lower alkyl or lower alkylthio, M is lithium or MgBr, and R ¹ , R ² and R ³ are as defined above)

The compound represented by the above formula (XVII) and the compound represented by the above formula (XVIII) in an inert solvent (eg, tetrahydrofuran, dioxane, etc.),
The compound represented by the above formula (VI) can be obtained by reacting at 20 ° C to the reflux temperature of the solvent used and, if necessary, performing an oxidation reaction according to a conventional method.

The compounds of the present invention and intermediates for the production thereof, and the above-mentioned formula (X) prepared by using the compounds of the present invention
Compounds such as III), (XV), (XVI) and (VIII) may be subjected to conventional isolation / purification means such as solvent extraction, recrystallization, chromatography and solid phase extraction, if necessary. Thus, it can be isolated and purified.

[0026]

BEST MODE FOR CARRYING OUT THE INVENTION The contents of the present invention will be described in more detail with reference to Examples, Reference Examples and Test Examples, which are intended to exemplify the present invention and limit the scope of the invention. is not.

[0027]

Example (Reference Example 1) A mixture of 3- (2-methylthiophenyl) -2-cyclohexen-1-one magnesium (12.9 g) and tetrahydrofuran (210 mL) was added with iodine (400 m) at room temperature.
g) and 2-bromothioanisole (7.6 g) were added at once, and the mixture was stirred at an external temperature of 50 ° C. After the reaction was started, a solution of 2-bromothioanisole (92.4 g) in tetrahydrofuran (210 mL) was added dropwise over 30 minutes,
The reaction mixture was stirred with heating under reflux for 1 hour and 20 minutes. Under the same conditions, a solution of 3-ethoxy-2-cyclohexen-1-one (53.1 g) in tetrahydrofuran (105 mL) was added dropwise, and the mixture was further stirred with heating under reflux for 2 hours. 2 mol / L hydrochloric acid (310 mL) was added dropwise to the reaction mixture under ice cooling. After stirring for 15 minutes under the same conditions, the reaction mixture was extracted twice with ethyl acetate (800 mL). Combine the organic layers,
It was washed with saturated saline (150 mL). The organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the solvent was evaporated under reduced pressure to give 3- (2-methylthiophenyl) -2-cyclohexen-1-one (100 g) as a reddish brown oil. It was

¹ H-NMR (CDCl ₃ ) δ ppm:
2.14-2.21 (2H, m), 2.45 (3H,
s), 2.50 (2H, t, J = 7.3Hz), 2.6
7 (2H, td, J = 6.0, 1.6Hz), 6.04
(1H, t, J = 1.6Hz), 7.08 (1H, d
d, J = 7.6, 1.3 Hz), 7.18 (1H, t
d, J = 7.3, 1.6 Hz), 7.27-7.35.
(2H, m)

Reference Example 2 3- (2-Methanesulfonylphenyl) -2-cyclohexen-1-one 3- (2-methylthiophenyl) -2-cyclohexen-1-one (59.0 g), acetone (500 mL) ) And water (100 mL) were added sodium hydrogencarbonate (195 g) with stirring under ice cooling. Subsequently, Oxone (registered trademark) (446 g) was added over 25 minutes, and the mixture was stirred at room temperature for 3 hours. A solution of sodium sulfite (26.5 g) in water (170 mL) was added to the reaction mixture under ice-cooling stirring, and the mixture was stirred for 25 minutes. Insoluble matter is filtered through Celite,
Celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. Water (500 mL) was added to the residue, and ethyl acetate (6
00 mL) and extracted twice. The combined organic layers were washed with saturated saline (200 mL) and dried over anhydrous magnesium sulfate. After removing the insoluble matter by filtration, the solvent was distilled off under reduced pressure, and 3- (2
-Methanesulfonylphenyl) -2-cyclohexene-
1-one (56.0 g) was obtained as an orange-brown oil.

¹ H-NMR (CDCl ₃ ) δ ppm:
2.15-2.30 (2H, m), 2.54 (2H, m
t, J = 6.8 Hz), 2.65-2.75 (2H,
m), 3.04 (3H, s), 5.94 (1H, t, J
= 1.6 Hz), 7.24 (1H, dd, J = 7.6,
1.1 Hz), 7.50-7.60 (1H, m), 7.
60-7.70 (1H, m), 8.09 (1H, dd,
J = 7.8, 1.0Hz)

Reference Example 3 4-Carbamoyl-2-methoxybenzenesulfonyl chloride 4-methoxybenzamide (150 g) was added little by little over 15 minutes to chlorosulfonic acid (1733 g) with stirring under ice cooling. After stirring the mixture at room temperature for 14 hours, 50
Stirred for an additional 1.5 hours at ° C. The reaction mixture was put on ice (7k
g), and the precipitate was collected by filtration and washed with water and hexane to give 5-carbamoyl-2-methoxybenzenesulfonyl chloride (230 g).

¹ H-NMR (DMSO-d ₆ ) δ pp
m: 3.81 (3H, s), 7.00 (1H, d, J
= 8.5 Hz), 7.10 (1H, brs), 7.84
(1H, dd, J = 8.5, 2.5Hz), 7.87
(1H, brs), 8.23 (1H, d, J = 2.5H
z)

Reference Example 4 5-Cyano-2-methoxybenzenesulfonyl chloride 5-carbamoyl-2-methoxybenzenesulfonyl chloride (150 g) was suspended in ethyl acetate (1.80 L) suspension under ice-cooling with stirring. Thionyl (219 mL) was added dropwise, N, N-dimethylformamide (2.30 mL) was added, and the mixture was stirred at 55 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. The separated organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to give 5-cyano-2-methoxybenzenesulfonyl chloride (86.8 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
4.16 (3H, s), 7.24 (1H, d, J = 8.
8 Hz), 7.96 (1H, dd, J = 8.8, 2.2)
Hz), 8.28 (1H, d, J = 2.2Hz)

Example 1 (3-Hydroxy-2'-methanesulfonylbiphenyl-4-yl) acetic acid 97% sulfuric acid (25.3 mL), water (50.7 mL) and 1,2-dimethoxyethane (600 mL). To the mixture under ice-cooling with stirring, 3- (2-methanesulfonylphenyl) -2-cyclohexen-1-one (118.9 g).
1,2-dimethoxyethane solution (360 mL) and glyoxylic acid monohydrate (131.2 g) were sequentially added.
The reaction mixture was stirred with heating under reflux for 18 hours. After allowing to cool to room temperature, water (360 mL) was added to the reaction mixture, and the mixture was extracted with toluene (300 mL). The aqueous layer was further extracted 3 times with a mixed solvent of tetrahydrofuran (360 mL) and toluene (120 mL). Combine the organic layers, 2 mol
/ L sodium hydroxide aqueous solution and extracted twice. The obtained aqueous layer was adjusted to pH 1 by adding concentrated hydrochloric acid under ice cooling, and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was removed by filtration, and the solvent was evaporated under reduced pressure to give a tan solid (3-hydroxy-2′-methanesulfonylbiphenyl-4-yl) acetic acid (97.5 g).

¹ H-NMR (DMSO-d ₆ ) δ pp
m: 2.82 (3H, s), 3.53 (2H, s),
6.78 (1H, dd, J = 7.8, 1.4Hz),
6.85 (1H, d, J = 1.4Hz), 7.18 (1
H, d, J = 7.8 Hz), 7.39 (1H, dd, J
= 7.5, 1.0 Hz), 7.60-7.70 (1H,
m), 7.70-7.80 (1H, m), 8.08 (1
H, dd, J = 7.7, 1.3 Hz), 9.70 (1
H, brs), 12.17 (1H, brs)

Example 2 (3-Hydroxy-2'-methanesulfonylbiphenyl-4-yl) acetamide (3-Hydroxy-2'-methanesulfonylbiphenyl-4-yl) acetic acid (47.02 g) in tetrahydrofuran ( Acetic anhydride (72.4 mL) was added to the solution (380 mL) at room temperature with stirring, and the mixture was stirred at 50 ° C. for 2 hours. 28% ammonia water (187 m) was added to the reaction mixture with stirring under ice cooling.
L) was added dropwise over 20 minutes, and after completion of the addition, the mixture was stirred at room temperature for 1 hour. After separating the organic layer, the aqueous layer was extracted 3 times with ethyl acetate (250 mL). The combined organic layer was washed with 150 mL of saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After the insoluble material was filtered off, the filtrate was evaporated under reduced pressure, water (250 mL) was added to the residue, and the mixture was stirred at room temperature for 1 hr. The obtained crystals were collected and washed with water (100 mL) to obtain (3-hydroxy-2′-methanesulfonylbiphenyl-4-yl) acetamide (30.4 g) as a light brown solid.

¹ H-NMR (DMSO-d ₆ ) δ pp
m: 2.83 (3H, s), 3.44 (2H, s),
6.79 (1H, dd, J = 7.8, 1.5Hz),
6.80-6.90 (1H, m), 7.03 (1H, b
rs), 7.15 (1H, d, J = 7.8Hz), 7.
38 (1H, dd, J = 7.5, 1.0 Hz), 7.4
6 (1H, brs), 7.60-7.70 (1H,
m), 7.70-7.80 (1H, m), 8.08 (1
H, dd, J = 7.5, 1.3 Hz), 9.96 (1
H, s)

Example 3 2- (3-Hydroxy-2'-methanesulfonylbiphenyl-4-yl) ethylamine (3-hydroxy-2'-methanesulfonylbiphenyl-4-yl) acetamide (3.78 g) 0.93 in a tetrahydrofuran (17 ml) suspension under stirring with ice cooling.
A tetrahydrofuran solution (40.0 mL) of M borane-tetrahydrofuran complex was added dropwise over 10 minutes. The reaction mixture was stirred at room temperature for 30 minutes, followed by heating under reflux for 3 hours. 2 mol / L to the reaction mixture with stirring under ice cooling
Hydrochloric acid (25.0 mL) was added dropwise while paying attention to foaming, and the mixture was stirred at room temperature for 30 minutes and subsequently at 50 ° C for 30 minutes. The reaction mixture was adjusted to pH 10 by adding a 2 mol / L sodium hydroxide aqueous solution (30.0 mL) under ice-cooling stirring, and extracted 3 times with ethyl acetate (60 mL). The combined organic layers were washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was removed by filtration, and the solvent was evaporated under reduced pressure to give a crude product (2.98 g). This crude product was converted into toluene-isopropanol (9:
1; 30.0 mL) and washed with 2- (3-hydroxy-
2'-Methanesulfonylbiphenyl-4-yl) ethylamine (2.62 g) was obtained.

¹ H-NMR (DMSO-d ₆ ) δ pp
m: 2.70 (2H, t, J = 5.7Hz), 2.80
(3H, s), 2.80-2.90 (2H, m), 6.
00-6.50 (2H, brs), 6.69 (1H, d
d, J = 7.6, 2.1 Hz), 6.73 (1H, d,
J = 2.1 Hz), 7.05 (1H, d, J = 7.6H
z), 7.37 (1H, dd, J = 7.6, 1.2H
z), 7.60-7.65 (1H, m), 7.65-
7.75 (1H, m), 8.07 (1H, dd, J =
(8.0, 1.3Hz)

Reference Example 5 5-Cyano-N- [2- (3-hydroxy-2'-methanesulfonylbiphenyl-4-yl) ethyl] -2-
Methoxybenzenesulfonamide 2- (3-hydroxy-2′-methanesulfonylbiphenyl-4-yl) ethylamine (120 g), tetrahydrofuran (1.56 L), triethylamine (287
mL) and methanol (504 mL) mixture,
Under stirring at 15 ° C, 5-cyano-2-methoxybenzenesulfonyl chloride (95.41 g) was added over 7 minutes, and the reaction mixture was stirred under the same conditions for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (960
mL) was added and dissolved, and a 1 mol / L aqueous sodium hydroxide solution (1.25 L) was added dropwise under stirring with ice cooling. The mixture was washed twice with toluene (480 mL) followed by toluene-tetrahydrofuran (600 mL). The aqueous layer was acidified by adding 2 mol / L hydrochloric acid (660 mL) under ice-cooling stirring, and extracted twice with ethyl acetate (570 mL). The combined organic layers were washed with saturated brine (240 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and 5-cyano-N- [2- (3-
Hydroxy-2'-methanesulfonylbiphenyl-4
-Yl) ethyl] -2-methoxybenzenesulfonamide (158.96 g) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ ppm:
2.69 (3H, s), 2.87 (2H, t, J = 6.
9 Hz), 3.20-3.30 (2H, m), 3.98
(3H, s), 5.34 (1H, t, J = 5.7H
z), 5.93 (1H, s), 6.88 (1H, dd,
J = 7.6, 1.6 Hz), 6.97 (1H, d, 1.
6 Hz), 7.05-7.15 (2H, m), 7.33
(1H, dd, J = 7.6, 1.3 Hz), 7.56
(1H, td, J = 7.6, 1.3 Hz), 7.65
(1H, td, J = 7.6, 1.3 Hz), 7.82
(1H, dd, J = 8.5, 2.2Hz), 8.15-
8.25 (2H, m)

Reference Example 6 Ethyl 5-cyano-N- [2] [4- [2- (5-cyano-2-methoxybenzenesulfonylamino) ethyl] -2'-methanesulfonylbiphenyl-3-yloxy] acetate N-N of-(3-hydroxy-2'-methanesulfonylbiphenyl-4-yl) ethyl] -2-methoxybenzenesulfonamide (5.72 g)
-N, N-diisopropylethylamine (2.46 mL) and ethyl bromoacetate (1.37 mL) were added to the dimethylformamide (57 mL) solution, and the mixture was stirred at 50 ° C for 15 hr. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (150 mL) -toluene (20 mL). The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by aminopropylated silica gel chromatography (elution solvent: ethyl acetate-hexane) to give amorphous [4- [2- (5-cyano-2-methoxybenzenesulfonylamino)]. Ethyl] -2'-methanesulfonylbiphenyl-3-yloxy] ethyl acetate (2.96 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm:
1.28 (3H, t, J = 6.9Hz), 2.59 (3
H, s), 2.95 (2H, t, J = 6.6 Hz),
3.30-3.60 (2H, m), 3.99 (3H,
s), 4.23 (2H, q, J = 6.9Hz), 4.6
8 (2H, s), 5.43 (1H, t, J = 6.3H
z), 6.95 (1H, dd, J = 7.6, 1.6H
z), 7.04 (1H, d, J = 1.6 Hz), 7.0
9 (1H, d, J = 8.5Hz), 7.20 (1H,
d, J = 7.6 Hz), 7.36 (1H, dd, J =
7.6, 1.3 Hz), 7.57 (1H, td, J =
7.6, 1.3 Hz), 7.65 (1H, td, J =
7.6, 1.3 Hz), 7.80 (1H, dd, J =
8.5, 2.2 Hz), 8.20-8.25 (2H,
m)

Reference Example 7 Ethyl [4- [2- (5-cyano-2-hydroxybenzenesulfonylamino) ethyl] -2'-methanesulfonylbiphenyl-3-yloxy] acetate [4- [2- (5 -Cyano-2-methoxybenzenesulfonylamino) ethyl] -2'-methanesulfonylbiphenyl-3-yloxy] ethyl acetate (4.62 g) in N, N-dimethylformamide (40 mL) solution lithium chloride (1.03 g). Was added and the mixture was stirred at 140 ° C. for 2 hours. After returning the reaction mixture to room temperature, ethyl acetate (60
mL) -toluene (6 mL) -1 mol / L hydrochloric acid (32
mL) poured into the mixture. The organic layer is separated and the organic layer is 1m
The extract was washed with ol / L hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by aminopropylated silica gel column chromatography (eluting solvent: acetic acid-ethyl acetate) to give colorless amorphous [4- [2- (5-cyano-2-hydroxybenzene). Sulfonylamino) ethyl] -2′-methanesulfonylbiphenyl-3-yloxy] ethyl acetate (3.67 g) was obtained.

¹ H-NMR (DMSO-d ₆ ) δ pp
m: 1.14 (3H, t, J = 7.3Hz), 2.71
(3H, s), 2.75-2.82 (2H, m), 3.
07-3.16 (2H, m), 4.10 (2H, q, J
= 7.3 Hz), 4.75 (2H, s), 6.90-
6.95 (2H, m), 7.12 (1H, d, J = 8.
5Hz), 7.20-7.30 (1H, m), 7.38
(1H, dd, J = 7.6, 1.3Hz), 7.45-
7.60 (1H, brs), 7.65 (1H, td, J
= 7.6, 1.3 Hz), 7.75 (1H, td, J =
7.6, 1.3 Hz), 7.87 (1H, dd, J =
8.5, 2.2 Hz, 8.01 (1H, d, J = 2.
2 Hz), 8.07 (1H, dd, J = 7.6, 1.3
Hz), 11.80-12.30 (1H, br)

Reference Example 8 Ethyl [4- [2- (5-carbamimidoyl-2-hydroxybenzenesulfonylamino) ethyl] -2'-methanesulfonylbiphenyl-3-yloxy] acetate [4- [2- (5-Cyano-2-hydroxybenzenesulfonylamino) ethyl] -2'-methanesulfonylbiphenyl-3-yloxy] ethyl acetate (149 mg)
A saturated hydrogen chloride-ethanol (1.0 mL) suspension of was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. Ammonium acetate (206 mg) was added to a solution of the residue in ethanol (1.0 mL), and the mixture was stirred at room temperature for 13 hours. The white solid obtained by concentrating the reaction mixture under reduced pressure was water,
The mixture was triturated with ethyl acetate-ethanol sequentially and a white powder of [4- [2- (5-carbamimidoyl-2-hydroxybenzenesulfonylamino) ethyl] -2'-methanesulfonylbiphenyl-3-yloxy] ethyl acetate (1
41 mg) was obtained.

¹ H-NMR (DMSO-d ₆ ) δ pp
m: 1.13 (3H, t, J = 7.3Hz), 2.72
(3H, s), 2.75-2.85 (2H, m), 2.
90-3.00 (2H, m), 4.09 (2H, q, J
= 7.3 Hz), 4.76 (2H, s), 6.43 (1
H, d, J = 8.9 Hz), 6.90-6.95 (2
H, m), 7.20 (1H, d, J = 7.9 Hz),
7.39 (1H, dd, J = 7.6, 1.3Hz),
7.57 (1H, dd, J = 8.9, 2.3Hz),
7.65 (1H, td, J = 7.6, 1.3Hz),
7.74 (1H, td, J = 7.6, 1.3Hz),
7.85-8.15 (4H, m), 8.45-8.80
(2H, br)

Reference Example 9 [4- [2- (5-carbamimidoyl-2-hydroxybenzenesulfonylamino) ethyl] -2'-methanesulfonylbiphenyl-3-yloxy] acetic acid hydrochloride (Compound 1) Ethyl [4- [2- (5-carbamimidoyl-2-hydroxybenzenesulfonylamino) ethyl] -2'-methanesulfonylbiphenyl-3-yloxy] acetate (2
90 mg) in acetonitrile (1.0 mL) solution 2 m
ol / L aqueous sodium hydroxide solution (0.756 mL) was added, and the mixture was stirred at room temperature for 30 minutes. 2mo in the reaction mixture
l / L hydrochloric acid (1.26 mL) was added, and the mixture was concentrated under reduced pressure. Water was added to the residue, which was subjected to SAX, washed with water, and
% Eluted with 1 mol / L hydrochloric acid-acetonitrile. The eluate was concentrated under reduced pressure to give a white solid, [4- [2- (5-carbamimidoyl-2-hydroxybenzenesulfonylamino) ethyl] -2'-methanesulfonylbiphenyl-.
3-yloxy] acetic acid hydrochloride (260 mg) was obtained.

¹ H-NMR (DMSO-d ₆ ) δ pp
m: 2.73 (3H, s), 2.80 (2H, t, J =
7.3 Hz), 3.10 (2H, t, J = 7.3H)
z), 4.65 (2H, s), 6.85-6.95 (2
H, m), 7.16 (1H, d, J = 7.6 Hz),
7.23 (1H, d, J = 8.3Hz), 7.37 (1
H, dd, J = 7.3, 1.3 Hz), 7.66 (1
H, td, J = 7.6, 1.3 Hz), 7.75 (1
H, td, J = 7.6, 1.3 Hz), 7.89 (1
H, dd, J = 8.3, 2.1 Hz) 8.08 (1H,
dd, J = 7.9, 1.3 Hz), 8.17 (1H,
d, J = 2.1 Hz), 8.91 (2H, brs),
9.28 (2H, brs)

Test Example 1 Measurement of Inhibitory Activity of Activated Blood Coagulation Factor X As a test compound [4- [2- (5-carbamimidoyl-2-hydroxybenzenesulfonylamino) ethyl]
-2'-Methanesulfonylbiphenyl-3-yloxy] acetic acid / hydrochloride dimethyl sulfoxide solution 2.5μ
L, pH 8.4, 100 mM Tris / 200 mM sodium chloride buffer 187.5 μL and 1 mM S-22
22 (manufactured by Daiichi Pure Chemicals Co., Ltd.) was dispensed in an amount of 50 μL, and 10 μL of a solution of human activated blood coagulation factor X (manufactured by Calbio Chemie) adjusted to 0.6 U / mL with a gelatin-glycine buffer solution was added. Incubated at 37 ° C for 10 minutes. The reaction was stopped by adding 50 μL of 60% acetic acid aqueous solution, and the absorbance (405 nm) was measured using a microplate reader (Spectramax 250, manufactured by Molecular Device).

As a control, 2.5 μL of dimethylsulfoxide was added instead of the test compound solution, and as a blank, 10 μL of gelatin-glycine buffer solution was added instead of the human activated blood coagulation factor X solution. The concentration of the test compound (IC ₅₀ ) at which the absorbance of the control was inhibited by 50% was determined and used as an index of the activated blood coagulation factor X inhibitory activity. The results are as shown in Table 1.

[0053]

[Table 1]

[0054]

According to the manufacturing method of the present invention, the above formula (V
By using the 3-phenyl-2-cyclohexenone derivative represented by I) as a starting material, the biphenylethylamine derivative represented by the above formula (I) can be easily produced in high yield. Further, by using the biphenylethylamine derivative (I), the 5-amidino-2-hydroxybenzenesulfonamide derivative represented by the above formula (VIII) can be produced in a very short number of steps than in the starting material and in good yield. The biphenylethylamine derivative is extremely useful as an intermediate for producing an activated blood coagulation factor X inhibitor.

Continued front page    (72) Inventor Yoshihiro Terao             187-8 Kawabata, Matsuoka, Okada, Matsumoto City, Nagano Prefecture             Name 201 (72) Inventor Ritsu Suzuki             5462-9 Toyoshina, Toyoshina-cho, Minamiazumi-gun, Nagano Prefecture             Zumino Court A101 (72) Inventor Satoshi Akabane             4246 Sasaga, Matsumoto City, Nagano Prefecture F-term (reference) 4H006 AA01 AA02 AB24 AC52 BE14                       TA02 TB04

Claims (8)

[Claims] 1. Formula (I): (In the formula, R ¹ and R ² are groups independently selected from the group consisting of hydrogen atom, halogen atom, lower alkyl, lower alkylthio and lower alkylsulfonyl;
³ is a halogen atom, a lower alkyl, a lower alkylthio or a lower alkylsulfonyl group). 2. The compound according to claim 1, wherein R ¹ and R ² are hydrogen atoms, and R ³ is a lower alkylsulfonyl group. 3. Formula (II): (In the formula, R ¹ and R ² are groups independently selected from the group consisting of hydrogen atom, halogen atom, lower alkyl, lower alkylthio and lower alkylsulfonyl;
³ is a halogen atom, a lower alkyl, a lower alkylthio or a lower alkylsulfonyl group) and is reacted with a condensing agent to give a compound represented by the formula (III): (Wherein R ¹ , R ² and R ³ are as defined above)
A compound represented by formula (I) is prepared by reacting the compound represented by formula (III) with ammonia.
V) [Chemical 4] (Wherein R ¹ , R ² and R ³ are as defined above)
A compound represented by the formula (I) embedded image is produced, and the compound represented by the formula (IV) is subsequently reduced. (Wherein R ¹ , R ² and R ³ are as defined above)
The manufacturing method of the compound represented by. 4. The production method according to claim 3, wherein R ¹ and R ² are hydrogen atoms, and R ³ is a lower alkylsulfonyl group. 5. Formula (V): (In the formula, R ¹ and R ² are groups independently selected from the group consisting of hydrogen atom, halogen atom, lower alkyl, lower alkylthio and lower alkylsulfonyl;
³ is a halogen atom, a lower alkyl, a lower alkylthio or a lower alkylsulfonyl group, and R ⁴ is a carboxyl group or a carbamoyl group). 6. The compound according to claim 5, wherein R ¹ and R ² are hydrogen atoms, and R ³ is a lower alkylsulfonyl group. 7. Formula (VI): (In the formula, R ¹ and R ² are groups independently selected from the group consisting of hydrogen atom, halogen atom, lower alkyl, lower alkylthio and lower alkylsulfonyl;
³ is a halogen atom, a lower alkyl, a lower alkylthio or a lower alkylsulfonyl group) and a compound of the formula (VII) A compound represented by the formula (V): (Wherein R ¹ , R ² and R ³ are as defined above,
R ⁴ is a carboxyl group). 8. The production method according to claim 7, wherein R ¹ and R ² are hydrogen atoms, and R ³ is a lower alkylsulfonyl group.