JPH0761984A - Production of imidazopyridine derivative and intermediate therefor - Google Patents

Abstract

PURPOSE:To obtain an imidazopyridine derivative useful as an antihypertensive agent and a therapeutic agent for vascular lesion by an industrially excellent method and in high yield by cyclizing a specific compound in a reducing condition. CONSTITUTION:A 2-[N-(biphenyl-4-yl)methyl]alkylamido--3-nitropyridine derivative of the formula I[R<1> is H, Cl, etc.; R<2> is H or CH3; R<3> is a lower alkyl, lower alkoxy, etc.; R<4> is COOR<5> (R<5> is aryl, aralkyl, etc.) or the formula II] is cyclized or cyclized and dehalogenated under a reducing condition, e.g. by a method using Pd-C as a catalyst and H2 gas as a reducing agent, to obtain the objective compound of the formula III. Here, the compound of the formula I is, e.g. 2-[N-2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamide-5- bromo-4-methyl-3-nitropyridine, etc. The compound of the formula I can be obtained by bringing a compound of the formula IV to an acid amide, which is then subjected to N-alkylation.

Description

Detailed Description of the Invention

[0001]

The present invention relates to an antihypertensive agent and a vascular lesion therapeutic agent disclosed in JP-A-3-95181, JP-A-3-236377, Japanese Patent Application No. 4-328986, etc. 2-Alkyl-3- (biphenyl-4-yl) methyl-3H-, a precursor of useful angiotensin II receptor antagonists
A method for producing an imidazo [4,5-b] pyridine derivative (II),
And an intermediate useful in the production thereof.

[0002]

2. Description of the Prior Art Conventionally, 2-alkyl-3- (biphenyl-)
The 4-yl) methyl-3H-imidazo [4,5-b] pyridine derivative (II) is mainly prepared by nitrating a 2-aminopyridine derivative as described in JP-A-3-236377. As an amino-3-nitropyridine derivative,
Then, the compound is reduced to a 2,3-diaminopyridine derivative, and then cyclized simultaneously with N-acylation to form a 3H-imidazo [4,5-b] pyridine nucleus, and finally by a method of N-alkylation. Has been manufactured. The manufacturing process by this conventional method is shown in the following reaction formula.

[0003]

[Chemical 17]

Examples of the N-alkylation method for producing the target compound in this method include, for example, JP-A-3-236377.
In the publication, in the presence of a base such as sodium hydride, sodium methoxide, potassium t-butoxide, sodium carbonate or potassium carbonate in a solvent such as N, N-dimethylformamide, dimethylsulfoxide, acetonitrile and acetone. 3H-imidazo [4,5-b]
Reacting a pyridine derivative with an N-alkylating reagent to give 2
-Alkyl-3- (biphenyl-4-yl) methyl-3
A method for obtaining an H-imidazo [4,5-b] pyridine derivative (II) is disclosed, and it is disclosed in JP-A-63-23868 and JP-A-Hei.
In Japanese Patent Laid-Open No. 3-5480 and Japanese Patent Laid-Open No. 95181/1993, a similar method of N-alkylating an imidazole nucleus is used to prepare 3- (2'-
Alkoxycarbonylbiphenyl-4-yl) methyl-
3H-imidazo [4,5-b] pyridine derivative or
N-[(2'-alkoxycarbonylbiphenyl-4-
A method for making an yl) methyl] imidazole derivative is disclosed.

[0005]

[Problems to be Solved by the Invention] A conventional method for producing an imidazo [4,5-b] pyridine derivative starts with a step of nitrating a 2-aminopyridine derivative to give a 2-amino-3-nitropyridine derivative. . However, upon nitration, the 2-aminopyridine derivative is o (ortho), p (para)
In order to show the orientation, in addition to the desired o-position-substituted 2-amino-3-nitropyridine derivative, a p-position-substituted 2-amino-5-nitropyridine derivative is by-produced, and its formation The ratio of the 5-nitro-substituted compound, which does not require a ratio, is overwhelmingly high at about 80 to 90%, and the yield of the target product is low at about 10 to 20%. reference).

Further, after forming an imidazo [4,5-b] pyridine nucleus, N-alkylation of the NH group of the imidazole ring is carried out, but at that time also, a hydrogen atom is abstracted by a base to delocalize the electron. Isomerization of the imidazopyridine ring occurs due to the transition to the target 3-alkyl-
Besides the 3H-imidazo [4,5-b] pyridine derivative, a 1-alkyl-1H-imidazo [4,5-b] pyridine derivative and a 4-alkyl-4H-imidazo [4,4
There is also a problem that a by-product such as a 5-b] pyridine derivative is generated. Even in this reaction, the yield of the desired product is about 20-40%.
And low (see the above chemical reaction formula [Chemical Formula 17]).

As described above, in the conventional method for producing imidazopyridine, there are two processes in which the yield is very poor before the target compound is obtained.
In addition, it is not economically efficient and requires a lot of labor for separation and purification, which is not always satisfactory as an industrial production method. Therefore, an industrially excellent production method capable of producing a desired imidazopyridine derivative from a starting 2-aminopyridine derivative in a high yield has been desired.

Further, conventional 2-alkyl-3- (2'-
Alkoxycarbonylbiphenyl-4-yl) methyl-
The biphenyl side chain of the 3H-imidazo [4,5-b] pyridine derivative uses a 2- (4′-bromomethylphenyl) benzoic acid ester as described in JP-A-3-236377. It has been produced by the method of N-alkylation. However, 2- (4'-bromomethylphenyl)
In the production of benzoic acid ester, N-bromosuccinimide is used for bromination in the method disclosed in JP-A-63-23868, but this reagent is expensive and bromination is a radical reaction. Therefore, it has a drawback that it is not suitable for industrial production because the reaction is rapid and difficult to control.

2- (4'-bromomethylphenyl)
The benzoic acid ester has high activity and is easy to react, but on the other hand, it has poor stability and cannot be stored because of its high activity. Therefore, it had to be prepared as needed, and the workability was extremely poor. Furthermore, since it is highly active, it has a drawback that decomposition or side reaction is likely to occur during the reaction, and the purity of the N-alkylated product is low, and there are many kinds of by-products, so that purification was difficult. Therefore, a new method for producing an imidazopyridine derivative using an active biphenyl derivative (IV) which is excellent in reactivity, operability and product purity as an N-alkylating agent has been required.

[0010]

Therefore, the present inventors have found that the lower the yield of the step close to the final step in producing the target compound, the lower the efficiency as an industrial production method.
The highest priority has been given to improving the yield of the alkylation process, and we have conducted intensive studies to improve the nitration process. As a result, 2-
Amino-3-nitropyridine derivative (V) was amidated and then N-alkylated to give 2- [N- (biphenyl-4-
(I) methyl] alkylamido-3-nitropyridine derivative (I) and then cyclized under reducing conditions to achieve the intended purpose and to achieve 2-alkyl-3- (biphenyl-
The present invention has been completed by finding that 4-yl) methyl-3H-imidazo [4,5-b] pyridine derivative (II) can be produced.

It is also known that when a 2-aminopyridine derivative is brominated or chlorinated, a 2-amino-5-bromopyridine derivative or a 2-amino-5-chloropyridine derivative can be obtained in good yield [Journal. of American Chemical Society (JACS), 79, 6
421-6426, 1957., Journal of Organic
Chemistry (J. Org. Chem.), 24 , 1455-1460, 1959.]]. When we nitrate these 2-amino-5-halogenpyridine derivatives as starting materials, we obtain 5
It was also found that the 3-position can be selectively obtained because the − position is blocked by a halogen atom, and the problem of nitration in the conventional method can be solved.

Further, in the present invention, when the halogen atom at the 5-position is subjected to reductive cyclization in the final step, the halogen atom can be simultaneously replaced with a hydrogen atom for elimination, and the 5-position can be used as a protecting group for nitration. Although a halogen atom is introduced into, there is an advantage that a separate elimination reaction is not required, and it can be said that it is an industrially excellent method.

In addition to 2- (4'-bromomethylphenyl) benzoic acid ester which has been conventionally used for N-alkylation, 2- (4'-chloromethylphenyl)
Benzoic acid ester, 2- (4′-alkylsulfonyloxymethylphenyl) benzoic acid ester derivative, 2-
(4′-Arylsulfonyloxymethylphenyl) benzoate derivative, 4,4-dimethyl-2- (4 ′
-Hydroxymethylbiphenyl-2-yl) oxazoline, 4,4-dimethyl-2- (4'-halomethylbiphenyl-2-yl) oxazoline derivative, 4,4-dimethyl-2- (4'-alkylsulfonyloxymethyl) By using an active biphenyl derivative (IV) such as a biphenyl-2-yl) oxazoline derivative or a 4,4-dimethyl-2- (4′-arylsulfonyloxymethylbiphenyl-2-yl) oxazoline derivative, operability is improved. It was also found that an imidazopyridine derivative can be produced with high product purity, and the present invention has been completed. The outline of the reaction route in the present invention is shown by the following chemical reaction formula.

[0014]

[Chemical 18]

Therefore, an object of the present invention is to provide 2-alkyl-3- (biphenyl-4) which is a precursor of an angiotensin II receptor antagonist useful as an antihypertensive agent and a therapeutic agent for vascular lesions.
-Yl) methyl-3H-imidazo [4,5-b] pyridine derivative (II) industrially excellent method for producing the same.

The 2- [N- (biphenyl-4-yl) methyl] alkylamido-3-nitropyridine derivative (I) according to the present invention has the following chemical structural formula.

[0017]

[Chemical 19]

In the formula, R ¹ means a hydrogen atom or a halogen atom, and the halogen atom means a bromine atom or a chlorine atom. R ² represents a hydrogen atom or a methyl group, and R ³ represents a cycloalkyl group, a lower alkyl group or a lower alkoxy group. R ⁴ is a group represented by the following general formula

[0019]

[Chemical 20]

[Wherein R ⁵ is a lower alkyl group, a cycloalkyl group, an alkoxyalkyl group, a thioalkoxyalkyl group, a cycloether group, an aryl group, an aralkyl group,
An alkenyl group, an alkynyl group and a trialkylsilyl group are meant. ] Or a group represented by the following general formula.

[0021]

[Chemical 21]

Specific examples of R ³ include, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group as a cycloalkyl group, and a methyl group, an ethyl group, an n-propyl group, an i-propyl group as a lower alkyl group. , N-butyl group, i-butyl group, t-butyl group, amyl group,
A hexyl group or another alkyl group having 1 to 6 carbon atoms, as a lower alkoxy group, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, a butoxy group, a pentyloxy group,
Examples thereof include lower alkoxy groups having 1 to 6 carbon atoms such as hexyloxy group.

Specific examples of R ⁵ include, for example, a lower alkyl group such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t-butyl group and n-pentyl group. Group, i-pentyl group, t-pentyl group, hexyl group, octyl group, decyl group, and other alkyl groups having 1 to 10 carbon atoms, and cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group. ,
Methoxymethyl group, ethoxymethyl group, methoxyethyl group, ethoxyethyl group, methoxyethoxymethyl group, phenoxymethyl group, benzyloxymethyl group and the like as alkoxyalkyl group, and methylthiomethyl group, methylthioethyl group and ethyl as thioalkoxyalkyl group. Thiomethyl group, phenylthiomethyl group, benzylthiomethyl group, etc., cycloether group as tetrahydropyranyl group, tetrahydrofuranyl group, etc., aryl group as phenyl group, toluyl group, xylyl group, etc., aralkyl group as benzyl group , Phenethyl, methylbenzyl, trimethylbenzyl, nitrobenzyl, phenacyl, etc., alkenyl, allyl, propenyl, cinnamyl, etc., alkynyl, propargyl, etc. Trimethylsilyl group as Rushiriru group, triethylsilyl group, t- butyl dimethyl silyl group, i- propyl dimethylsilyl group, and phenyl dimethyl silyl group. Of these, preferred groups include a lower alkyl group, a cycloalkyl group, a methoxymethyl group, a tetrahydropyranyl group, a phenyl group,
Examples thereof include a benzyl group and a trimethylsilyl group.

The following compounds can be mentioned as more specific representative examples.
-(Biphenyl-4-yl) methyl] alkylamido-
The 3-nitropyridine derivative (I) is not limited to these.

(1) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] cyclopropanecarboxamido-4-methyl-3-nitropyridine (2) 2- [N- (2'-methoxy Carbonylbiphenyl-4-yl) methyl] cyclopropanecarboxamide-
4,6-Dimethyl-3-nitropyridine (3) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] cyclopropanecarboxamide-
5-Bromo-4-methyl-3-nitropyridine (4) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] cyclopropanecarboxamide-
5-chloro-4-methyl-3-nitropyridine (5) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] cyclopropanecarboxamide-
5-Bromo-4,6-dimethyl-3-nitropyridine (6) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] cyclopropanecarboxamide-
5-Chloro-4,6-dimethyl-3-nitropyridine (7) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] butyrylamino-4-methyl-3
-Nitropyridine (8) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] butyrylamino-4,6-dimethyl-3-nitropyridine (9) 2- [N- (2'-methoxy Carbonylbiphenyl-4-yl) methyl] butyrylamino-5-bromo-4
-Methyl-3-nitropyridine (10) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] butyrylamino-5-bromo-
4,6-Dimethyl-3-nitropyridine (11) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] valerylamino-4-methyl-
3-Nitropyridine (12) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] valerylamino-4,6-dimethyl-3-nitropyridine (13) 2- [N- (2'- Methoxycarbonylbiphenyl-4-yl) methyl] valerylamino-5-bromo-
4-Methyl-3-nitropyridine (14) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] valerylamino-5-bromo-
4,6-Dimethyl-3-nitropyridine (15) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] cyclopropanecarboxamide-4 -Methyl-3-
Nitropyridine (16) 2- [N- {2 '-(4 ", 4" -dimethyloxazoline-2 "-yl) biphenyl-4-yl} methyl] cyclopropanecarboxamide-4,6-dimethyl-3-nitro Pyridine (17) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] cyclopropanecarboxamido-5-bromo-4-
Methyl-3-nitropyridine (18) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] cyclopropanecarboxamide-5-chloro-4 −
Methyl-3-nitropyridine (19) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] cyclopropanecarboxamide-5-bromo-4 ，
6-Dimethyl-3-nitropyridine (20) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] cyclopropanecarboxamide-5-chloro -4
6-Dimethyl-3-nitropyridine (21) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] butyrylamino-4-methyl-3 -Nitropyridine (22) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] butyrylamino-4,6-dimethyl-3-nitropyridine (23) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] butyrylamino-5-bromo-4-methyl-3-nitropyridine ( 24) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] butyrylamino-5-bromo-4,6-dimethyl-
3-Nitropyridine (25) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] valerylamino-4-methyl-3-nitropyridine ( 26) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] valerylamino-4,6-dimethyl-3-nitropyridine (27) 2 -[N- {2 '-(4 ", 4" -dimethyloxazoline-2 "-yl) biphenyl-4-yl} methyl] valerylamino-5-bromo-4-methyl-3-nitropyridine (28) 2- [N- {2 '-(4 ", 4" -dimethyloxazoline-2 "-yl) biphenyl-4-yl} methyl] valerylamino-5-bromo-4,6-dimethyl-
3-nitropyridine

Further, 2-alkyl-3- in the present invention
The (biphenyl-4-yl) methyl-3H-imidazo [4,5-b] pyridine derivative (II) is represented by the following chemical structural formula.

[0027]

[Chemical formula 22]

In the formula, R ² , R ³ and R ⁴ have the same meanings as described above. The following compounds can be given as more specific representative examples, but 2-alkyl-3- (biphenyl-4-yl) methyl-3H- according to the present invention.
The imidazo [4,5-b] pyridine derivative (II) is not limited to these.

(1) 2-Cyclopropyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-7-
Methyl-3H-imidazo [4,5-b] pyridine (2) 2-cyclopropyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-5,7-dimethyl-3H-imidazo [4,5] -B] pyridine (3) 2-n-propyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-7-methyl-3H-imidazo [4,5-b] pyridine (4) 2-n -Propyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-5,7-dimethyl-3
H-imidazo [4,5-b] pyridine (5) 2-n-butyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-7-methyl-3H-imidazo [4,5-b] Pyridine (6) 2-n-butyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-5,7-dimethyl-3H
-Imidazo [4,5-b] pyridine (7) 2-ethyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-7-methyl-3H-imidazo [4,5-b] pyridine (8 ) 2-Ethyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-5,7-dimethyl-3H-
Imidazo [4,5-b] pyridine (9) 2-cyclopropyl-3- [2 '-(4 ", 4"-
Dimethyloxazoline-2 "-yl) biphenyl-4-
Il] methyl-7-methyl-3H-imidazo [4,5-
b] pyridine (10) 2-cyclopropyl-3- [2 '-(4 ", 4"
-Dimethyloxazoline-2 "-yl) biphenyl-4
-Yl] methyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (11) 2-n-propyl-3- [2 '-(4 ", 4" -dimethyloxazoline-2 "- Il) biphenyl-4-yl] methyl-7-methyl-3H-imidazo [4,5-
b] Pyridine (12) 2-n-propyl-3- [2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl] methyl-5,7-dimethyl-3H-imidazo [4
5-b] Pyridine (13) 2-n-butyl-3- [2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl] methyl-7-methyl-3H-imidazo [4,5-
b] Pyridine (14) 2-n-butyl-3- [2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl] methyl-5,7-dimethyl-3H-imidazo [4
5-b] pyridine (15) 2-ethyl-3- [2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl]
Methyl-7-methyl-3H-imidazo [4,5-b] pyridine (16) 2-ethyl-3- [2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl ]
Methyl-5,7-dimethyl-3H-imidazo [4,5-
b] pyridine

Further, the 2-alkylamido-3-nitropyridine derivative (III) obtained as a result of step 1 is represented by the following chemical structural formula.

[0031]

[Chemical formula 23]

In the formula, R ¹ , R ² and R ³ have the same meanings as described above. More specifically, for example, the following compounds can be mentioned, but 2-alkylamide-
The 3-nitropyridine derivative (III) is not limited to these.

(1) 2-cyclopropanecarboxamide-
4-Methyl-3-nitropyridine (2) 2-Cyclopropanecarboxamide-4,6-dimethyl-3-nitropyridine (3) 2-Cyclopropanecarboxamide-5-bromo-
4-Methyl-3-nitropyridine (4) 2-cyclopropanecarboxamide-5-chloro-
4-Methyl-3-nitropyridine (5) 2-cyclopropanecarboxamide-5-bromo-
4,6-Dimethyl-3-nitropyridine (6) 2-Cyclopropanecarboxamide-5-chloro-
4,6-Dimethyl-3-nitropyridine (7) 2-butyrylamino-4-methyl-3-nitropyridine (8) 2-butyrylamino-4,6-dimethyl-3-nitropyridine (9) 2-butyrylamino-5 -Bromo-4-methyl-3
-Nitropyridine (10) 2-butyrylamino-5-bromo-4,6-dimethyl-3-nitropyridine (11) 2-valerylamino-4-methyl-3-nitropyridine (12) 2-valerylamino-4,6- Dimethyl-3-nitropyridine (13) 2-valerylamino-5-bromo-4-methyl-
3-Nitropyridine (14) 2-valerylamino-5-bromo-4,6-dimethyl-3-nitropyridine

The active biphenyl derivative (IV) according to the present invention is represented by the following general formula.

[0035]

[Chemical formula 24]

In the formula, Y means a hydroxyl group, a halogen atom, a lower alkylsulfonyloxy group or an arylsulfonyloxy group, and R ⁴ has the same meaning as described above. Specifically, as the halogen atom, for example, chlorine atom, bromine atom, iodine atom, fluorine atom and the like, and as the lower alkylsulfonyloxy group, for example, methanesulfonyloxy group, ethanesulfonyloxy group and the like having 1 to 6 lower carbon atoms. A group having an alkyl group in the molecule is used as an arylsulfonyloxy group such as a benzenesulfonyloxy group, p-
A toluene sulfonyloxy group etc. can be mentioned.
More specifically, for example, the following compounds can be mentioned, but the active biphenyl derivative (IV) according to the present invention is not limited thereto. Incidentally, these compounds are disclosed in JP-A-3-
Japanese Patent Application No. 236377, Japanese Patent Application No. 5-169823, Japanese Patent Application No. 5-169824,
It can be obtained according to the method disclosed in Japanese Patent Application No. 5-169825.

(1) Methyl 2- (4'-hydroxymethylphenyl) benzoate (2) Methyl 3- (4'-hydroxymethylphenyl) benzoate (3) 4- (4'-hydroxymethylphenyl) benzoic acid Methyl (4) ethyl 2- (4'-hydroxymethylphenyl) benzoate (5) ethyl 3- (4'-hydroxymethylphenyl) benzoate (6) ethyl 4- (4'-hydroxymethylphenyl) benzoate ( 7) Propyl 2- (4'-hydroxymethylphenyl) benzoate (8) Butyl 2- (4'-hydroxymethylphenyl) benzoate (9) Phenyl 2- (4'-hydroxymethylphenyl) benzoate (10) Benzyl 2- (4'-hydroxymethylphenyl) benzoate (11) Tetrahydropyranyl 2- (4'-hydroxymethylphenyl) benzoate (12) 2- (4'-hydroxymethylphenyl) Tetrahydrofuranyl benzoate (13) 2- (4'-hydroxymethylphenyl) trimethylsilyl benzoate (14) 2- (4'-hydroxymethylphenyl) methoxymethyl benzoate (15) 2- (4'-hydroxymethylphenyl) Thiomethoxymethyl benzoate (16) Methyl 2- (4'-bromomethylphenyl) benzoate (17) 3- (4'-Bromomethylphenyl) methyl benzoate (18) 4- (4'-Bromomethylphenyl) Methyl benzoate (19) Methyl 2- (4'-chloromethylphenyl) benzoate (20) Methyl 3- (4'-chloromethylphenyl) benzoate (21) 4- (4'-chloromethylphenyl) benzoic acid Methyl (22) Methyl 2- (4'-methanesulfonyloxymethylphenyl) benzoate (23) Methyl 3- (4'-methanesulfonyloxymethylphenyl) benzoate (24) 4 Methyl (4'-methanesulfonyloxymethylphenyl) benzoate (25) Ethyl 2- (4'-methanesulfonyloxymethylphenyl) benzoate (26) Ethyl 3- (4'-methanesulfonyloxymethylphenyl) benzoate ( 27) Ethyl 4- (4'-methanesulfonyloxymethylphenyl) benzoate (28) Methyl 2- (4'-ethanesulfonyloxymethylphenyl) benzoate (29) 3- (4'-ethanesulfonyloxymethylphenyl) Methyl benzoate (30) Methyl 4- (4'-ethanesulfonyloxymethylphenyl) benzoate (31) Ethyl 2- (4'-ethanesulfonyloxymethylphenyl) benzoate (32) 3- (4'-ethanesulfonyl) Ethyl oxymethylphenyl) benzoate (33) Ethyl 4- (4'-ethanesulfonyloxymethylphenyl) benzoate (34) 2 Methyl (4'-p-toluenesulfonyloxymethylphenyl) benzoate (35) Methyl 3- (4'-p-toluenesulfonyloxymethylphenyl) benzoate (36) 4- (4'-p-toluenesulfonyloxymethyl) Phenyl) methyl benzoate (37) Ethyl 2- (4'-p-toluenesulfonyloxymethylphenyl) benzoate (38) Ethyl 3- (4'-p-toluenesulfonyloxymethylphenyl) benzoate (39) 4- Ethyl (4'-p-toluenesulfonyloxymethylphenyl) benzoate (40) Methyl 2- (4'-benzenesulfonyloxymethylphenyl) benzoate (41) 3- (4'-benzenesulfonyloxymethylphenyl) benzoic acid Methyl (42) 4- (4'-benzenesulfonyloxymethylphenyl) methyl benzoate (43) 2- (4'-benzenesulfonyloxymethylphenyl) Nyl) ethyl benzoate (44) Ethyl 3- (4'-benzenesulfonyloxymethylphenyl) benzoate (45) Ethyl 4- (4'-benzenesulfonyloxymethylphenyl) benzoate (46) 4,4-Dimethyl- 2- (4'-hydroxymethylbiphenyl-2-yl) oxazoline (47) 4,4-dimethyl-2- (4'-bromomethylbiphenyl-2-yl) oxazoline (48) 4,4-dimethyl-2 -(4'-Chloromethylbiphenyl-2-yl) oxazoline (49) 4,4-dimethyl-2- (4'-methanesulfonyloxymethylbiphenyl-2-yl) oxazoline (50) 4,4-dimethyl-2 -(4'-ethanesulfonyloxymethylbiphenyl-2-yl) oxazoline (51) 4,4-dimethyl-2- (4'-benzenesulfonyloxymethylbiphenyl-2- Yl) oxazoline (52) 4,4-dimethyl-2- [4 '-(p-toluenesulfonyloxymethyl) biphenyl-2-yl) oxazoline

The 2-amino-3-nitropyridine derivative (V) according to the present invention is a known substance and is represented by the following general formula.

[0039]

[Chemical 25]

In the formula, R ¹ and R ² have the same meanings as described above. More specifically, for example, the following compounds can be mentioned, but the 2-amino-3-nitropyridine derivative (V) according to the present invention is not limited thereto. (1) 2-Amino-4-methyl-3-nitropyridine (2) 2-amino-4,6-dimethyl-3-nitropyridine (3) 2-amino-5-bromo-4-methyl-3-nitro Pyridine (4) 2-Amino-5-chloro-4-methyl-3-nitropyridine (5) 2-Amino-5-bromo-4,6-dimethyl-3-
Nitropyridine (6) 2-amino-5-chloro-4,6-dimethyl-3-
Nitropyridine

Further, 2- [N- obtained by carrying out step 8
The (biphenyl-4-yl) methyl] amino-3-alkylamidopyridine derivative (VI) is represented by the following general formula.

[0042]

[Chemical formula 26]

In the formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above. More specifically, for example, the following compounds can be mentioned, but the 2- [N- (biphenyl-4-yl) methyl] amino-3-alkylamidopyridine derivative (VI) according to the present invention is limited to these. Not done.

(1) 3-cyclopropanecarboxamide-
2- [N- (2'-methoxycarbonylbiphenyl-4
-Yl) methyl] amino-4-methylpyridine (2) 3-cyclopropanecarboxamide-2- [N-
(2'-Methoxycarbonylbiphenyl-4-yl) methyl] amino-4,6-dimethylpyridine (3) 3-cyclopropanecarboxamide-2- [N-
(2′-Methoxycarbonylbiphenyl-4-yl) methyl] amino-5-bromo-4-methylpyridine (4) 3-cyclopropanecarboxamide-2- [N-
(2'-Methoxycarbonylbiphenyl-4-yl) methyl] amino-5-chloro-4-methylpyridine (5) 3-cyclopropanecarboxamide-2- [N-
(2'-Methoxycarbonylbiphenyl-4-yl) methyl] amino-5-bromo-4,6-dimethylpyridine (6) 3-cyclopropanecarboxamide-2- [N-
(2'-Methoxycarbonylbiphenyl-4-yl) methyl] amino-5-chloro-4,6-dimethylpyridine (7) 3-butyrylamino-2- [N- (2'-methoxycarbonylbiphenyl-4-yl) Methyl] amino-4
-Methylpyridine (8) 3-butyrylamino-2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] amino-
4,6-Dimethylpyridine (9) 3-butyrylamino-2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] amino-5
-Bromo-4-methylpyridine (10) 3-butyrylamino-2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] amino-
5-Bromo-4,6-dimethylpyridine (11) 3-valerylamino-2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] amino-
4-Methylpyridine (12) 3-valerylamino-2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] amino-
4,6-Dimethylpyridine (13) 3-valerylamino-2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] amino-
5-Bromo-4-methylpyridine (14) 3-valerylamino-2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] amino-
5-Bromo-4,6-dimethylpyridine (15) 3-cyclopropanecarboxamide-2- [N-
{2 '-(4 ", 4" -dimethyloxazoline-2 "-
Iyl) biphenyl-4-yl} methyl] amino-4-methylpyridine (16) 3-cyclopropanecarboxamide-2- [N-
{2 '-(4 ", 4" -dimethyloxazoline-2 "-
Il) biphenyl-4-yl} methyl] amino-4,6
-Dimethylpyridine (17) 3-Cyclopropanecarboxamide-2- [N-
{2 '-(4 ", 4" -dimethyloxazoline-2 "-
Iyl) biphenyl-4-yl} methyl] amino-5-bromo-4-methylpyridine (18) 3-cyclopropanecarboxamide-2- [N-
{2 '-(4 ", 4" -dimethyloxazoline-2 "-
Iyl) biphenyl-4-yl} methyl] amino-5-chloro-4-methylpyridine (19) 3-cyclopropanecarboxamide-2- [N-
{2 '-(4 ", 4" -dimethyloxazoline-2 "-
Iyl) biphenyl-4-yl} methyl] amino-5-bromo-4,6-dimethylpyridine (20) 3-cyclopropanecarboxamide-2- [N-
{2 '-(4 ", 4" -dimethyloxazoline-2 "-
Iyl) biphenyl-4-yl} methyl] amino-5-chloro-4,6-dimethylpyridine (21) 3-butyrylamino-2- [N- {2'-
(4 ", 4" -Dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] amino-4-methylpyridine (22) 3-butyrylamino-2- [N- {2'-
(4 ", 4" -Dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] amino-4,6-dimethylpyridine (23) 3-butyrylamino-2- [N- {2'-
(4 ", 4" -Dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] amino-5-bromo-4
-Methylpyridine (24) 3-butyrylamino-2- [N- {2'-
(4 ", 4" -Dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] amino-5-bromo-
4,6-Dimethylpyridine (25) 3-valerylamino-2- [N- {2'-
(4 ", 4" -Dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] amino-4-methylpyridine (26) 3-valerylamino-2- [N- {2'-
(4 ", 4" -Dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] amino-4,6-dimethylpyridine (27) 3-valerylamino-2- [N- {2'-
(4 ", 4" -Dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] amino-5-bromo-4
-Methylpyridine (28) 3-valerylamino-2- [N- {2'-
(4 ", 4" -Dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] amino-5-bromo-
4,6-dimethylpyridine

Next, 2-alkyl-3- (biphenyl-4)
-Yl) methyl-6-halogen-3H-imidazo [4,
The 5-b] pyridine derivative (VII) is represented by the following general formula.

[0046]

[Chemical 27]

In the formula, X is a halogen atom, R ² , R ³ and R ⁴
Has the same meaning as described above. Further, the halogen atom means a bromine atom or a chlorine atom. More specifically, for example, the following compounds can be mentioned. 2-alkyl-3- (biphenyl-4-yl) according to the present invention
Methyl-6-halogen-3H-imidazo [4,5-b]
The pyridine derivative (VII) is not limited to these.

(1) 2-cyclopropyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-6-
Bromo-7-methyl-3H-imidazo [4,5-b] pyridine (2) 2-cyclopropyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-6-chloro-7-
Methyl-3H-imidazo [4,5-b] pyridine (3) 2-cyclopropyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-6-bromo-5.
7-Dimethyl-3H-imidazo [4,5-b] pyridine (4) 2-cyclopropyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-6-chloro-5.
7-Dimethyl-3H-imidazo [4,5-b] pyridine (5) 2-n-propyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-6-bromo-7-methyl-3H- Imidazo [4,5-b] pyridine (6) 2-n-propyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-6-chloro-7-methyl-3H-imidazo [4,5- b] Pyridine (7) 2-n-propyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-6-bromo-5,7-
Dimethyl-3H-imidazo [4,5-b] pyridine (8) 2-n-propyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-6-chloro-5,7-
Dimethyl-3H-imidazo [4,5-b] pyridine (9) 2-n-butyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-6-bromo-7-methyl-3H-imidazo [ 4,5-b] Pyridine (10) 2-n-butyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-6-chloro-7-methyl-3H-imidazo [4,5-b] Pyridine (11) 2-n-butyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-6-bromo-5,7-
Dimethyl-3H-imidazo [4,5-b] pyridine (12) 2-n-butyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-6-chloro-5,7-
Dimethyl-3H-imidazo [4,5-b] pyridine (13) 2-ethyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-6-bromo-7-methyl-3H-imidazo [4. 5-b] pyridine (14) 2-ethyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-6-chloro-7-methyl-3H-imidazo [4,5-b] pyridine (15) 2-Ethyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-6-bromo-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (16) 2-ethyl-3- (2'-Methoxycarbonylbiphenyl-4-yl) methyl-6-chloro-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (17) 2-cyclopropyl-3- [2 '-( 4 ", 4"
-Dimethyloxazoline-2 "-yl) biphenyl-4
-Yl] methyl-6-bromo-7-methyl-3H-imidazo [4,5-b] pyridine (18) 2-cyclopropyl-3- [2 '-(4 ", 4"
-Dimethyloxazoline-2 "-yl) biphenyl-4
-Yl] methyl-6-chloro-7-methyl-3H-imidazo [4,5-b] pyridine (19) 2-cyclopropyl-3- [2 '-(4 ", 4"
-Dimethyloxazoline-2 "-yl) biphenyl-4
-Yl] methyl-6-bromo-5,7-dimethyl-3H
-Imidazo [4,5-b] pyridine (20) 2-cyclopropyl-3- [2 '-(4 ", 4"
-Dimethyloxazoline-2 "-yl) biphenyl-4
-Yl] methyl-6-chloro-5,7-dimethyl-3H
-Imidazo [4,5-b] pyridine (21) 2-n-propyl-3- [2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl] methyl-6- Bromo-7-methyl-3H-imidazo [4,5-b] pyridine (22) 2-n-propyl-3- [2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4 -Yl] methyl-6-chloro-7-methyl-3H-imidazo [4,5-b] pyridine (23) 2-n-propyl-3- [2 '-(4 ", 4" -dimethyloxazoline-2 "-Yl) biphenyl-4-yl] methyl-6-bromo-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (24) 2-n-propyl-3- [2 '-(4 ", 4" -Dimethyloxazolin-2 "-yl) biphenyl-4-yl] methyl-6-chloro-5, -Dimethyl-3H-imidazo [4,5-b] pyridine (25) 2-n-butyl-3- [2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl] Methyl-6-bromo-7-methyl-3H-imidazo [4,5-b] pyridine (26) 2-n-butyl-3- [2 '-(4 ", 4" -dimethyloxazolin-2 "-yl ) Biphenyl-4-yl] methyl-6-chloro-7-methyl-3H-imidazo [4,5-b] pyridine (27) 2-n-butyl-3- [2 '-(4 ", 4"- Dimethyloxazoline-2 "-yl) biphenyl-4-yl] methyl-6-bromo-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (28) 2-n-butyl-3- [2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl] methyl-6-quat Rho-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (29) 2-ethyl-3- [2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4 -Ill]
Methyl-6-bromo-7-methyl-3H-imidazo [4,5-b] pyridine (30) 2-ethyl-3- [2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl -4-yl]
Methyl-6-chloro-7-methyl-3H-imidazo [4,5-b] pyridine (31) 2-ethyl-3- [2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl -4-yl]
Methyl-6-bromo-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (32) 2-ethyl-3- [2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) ) Biphenyl-4-yl]
Methyl-6-chloro-5,7-dimethyl-3H-imidazo [4,5-b] pyridine

The 2- [N- (biphenyl-4-yl) methyl] alkylamido-3-nitropyridine derivative (VIII) is represented by the following general formula.

[0050]

[Chemical 28]

In the formula, R ² , R ³ and R ⁴ have the same meanings as described above. More specifically, for example, the following compounds can be mentioned, but the 2- [N- (biphenyl-4-yl) methyl] alkylamido-3-nitropyridine derivative (VIII) according to the present invention is not limited to these. Not done.

(1) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] cyclopropanecarboxamido-4-methyl-3-nitropyridine (2) 2- [N- (2'-methoxy Carbonylbiphenyl-4-yl) methyl] cyclopropanecarboxamide-
4,6-Dimethyl-3-nitropyridine (3) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] butyrylamino-4-methyl-3
-Nitropyridine (4) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] butyrylamino-4,6-dimethyl-3-nitropyridine (5) 2- [N- (2'-methoxy Carbonylbiphenyl-4-yl) methyl] valerylamino-4-methyl-3
-Nitropyridine (6) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] valerylamino-4,6-dimethyl-3-nitropyridine (7) 2- [N- {2 '-( 4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl]
Cyclopropanecarboxamido-4-methyl-3-nitropyridine (8) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl]
Cyclopropane carboxamide-4,6-dimethyl-3
-Nitropyridine (9) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl]
Butyrylamino-4-methyl-3-nitropyridine (10) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] butyrylamino-4,6 -Dimethyl-3-nitropyridine (11) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] valerylamino-4-methyl-3- Nitropyridine (12) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl] valerylamino-4,6-dimethyl-3-nitropyridine

Next, the 2-alkylamido-3-nitropyridine derivative (IX) is represented by the following general formula.

[0054]

[Chemical 29]

In the formula, R ² and R ³ have the same meanings as described above. More specifically, for example, the following compounds can be mentioned, but 2-alkylamide-3- according to the present invention
The nitropyridine derivative (IX) is not limited to these.

(1) 2-cyclopropanecarboxamide-
4-Methyl-3-nitropyridine (2) 2-cyclopropanecarboxamide-4,6-dimethyl-3-nitropyridine (3) 2-butyrylamino-4-methyl-3-nitropyridine (4) 2-butyrylamino-4 , 6-Dimethyl-3-nitropyridine (5) 2-valerylamino-4-methyl-3-nitropyridine (6) 2-valerylamino-4,6-dimethyl-3-nitropyridine

Next, each step of the production method according to the present invention will be described in detail below (see the chemical reaction formula [Chemical Formula 18]). Step 1 This step is a 2-amino-3-nitropyridine derivative (V)
Is reacted with a compound represented by the general formula R ³ COZ or (R ³ CO) ₂ O to form an acid amid, and a 2-alkylamide-
In this step, the 3-nitropyridine derivative (III) is obtained. In this step, an acid chloride (Z = halogen atom in the above general formula R ³ COZ) and a carboxylic acid (also Z = O) are used.
H), mixed acid anhydride (Z = alkoxycarbonyl group, aryloxycarbonyl group, aralkyloxycarbonyl group, etc.), acid anhydride [the above general formula (R ³ CO) ₂ O] or carboxylic acid and N-hydroxybenztriazole Alternatively, acid amidation is carried out by a conventional method using an active ester such as N-hydroxysuccinimide.

Step 2 In this step, the 2-alkylamido-3-nitropyridine derivative (III) is treated with the active biphenyl derivative (IV) in N 2
-Alkylated, 2- [N- (biphenyl-4-yl)
Methyl] alkylamido-3-nitropyridine derivative
This is a step of producing (I).

Step 3 In this step, 2- [N- (biphenyl-4-yl) methyl] alkylamido-3-nitropyridine derivative (I) was cyclized under reducing conditions to give 2-alkyl-3- (biphenyl). -4-yl) methyl-3H-imidazo [4,5-b] pyridine derivative (II) is prepared. Specific examples of the catalyst and reducing agent in that case include the following combinations (catalyst and reducing agent).

A) Palladium-carbon (hereinafter, Pd-C), amine / organic acid b) Pd-C, hydrogen gas C) Sodium borohydride / cupric chloride d) Pd-C, sodium hypophosphite (NaH ₂ PO ₂ ) e) Pd-C, iron / acetic acid

The Pd-C catalyst according to the present invention is not limited as long as it is generally used for catalytic reduction reaction, but usually the palladium content is 2 to 20%, preferably 5 to 10%. %belongs to. The shape is not limited, and may be a dry powder, a wet body, or a water-containing slurry. The amount used is also not limited, but usually 0.001 to the compound (I)
It is 10% by weight, preferably 0.01-5% by weight, more preferably 0.1-1% by weight.

The organic acid according to the present invention means a lower carboxylic acid having 1 to 6 carbon atoms, and specific examples thereof include formic acid, acetic acid and propionic acid.

The amine according to the present invention is not limited as long as it can form a salt with an organic acid such as formic acid or acetic acid. Specific examples of commonly used amines include triethylamine, trimethylamine and tripropylamine. Diethylamine, dimethylamine, dipropylamine, diisopropylamine, dibutylamine, N,
N-dimethylethylamine, N, N-dimethylpropylamine, N, N-dimethylisopropylamine, N, N
-Dimethylbutylamine, N, N-dimethylhexylamine, N, N-dimethylcyclohexylamine, N, N
-Dimethyloctylamine, N, N-dimethyldodecylamine, N, N-dimethylbenzylamine, N, N-dimethyl-2-chloroethylamine, N, N-dimethyl-
2-chloropropylamine, 2-chlorotriethylamine, N, N-diethylmethylamine, N, N, N ',
N'-tetramethylmethanediamine, N, N, N ',
N'-tetramethylethylenediamine, N, N-dimethylaniline, N, N-dimethyltoluidine, N, N-diethylaniline, ethanolamine, diethanolamine, triethanolamine, N-methylethanolamine, N, N-dimethylethanolamine , Pyridine, N
-Methylpiperidine, N-methylmorpholine, 1,4-
Examples thereof include dimethylpiperazine, N-methylpyrrole, N-methylpyrrolidine, and ammonia. Among these amines, triethylamine, trimethylamine, tripropylamine, diethylamine, and ethanolamine are more preferable, and triethylamine is further preferable.

When triethylamine formic acid is used as a reducing agent, it is generally described in Journal of Organic Chemistry (J. Org. Chem.), 42 (22), 3491-3494, 1977.
The amount of amine used in the present invention is usually 1 to 150 with respect to compound (I).
It is an equivalent, preferably 1.5 to 50 equivalents, and more preferably 2 to 20 equivalents. The amount of the organic acid used is usually 1 to 50 equivalents relative to compound (I), preferably 1.
It is 5 to 20 equivalents, and more preferably 2 to 10 equivalents.

Furthermore, in the present invention, a Pd-C catalyst and an amine
The reduction / cyclization with a combination of organic acids can be carried out without solvent or in a solvent. When a solvent is used, specific examples include water, methanol, ethanol, n-propanol, i-propanol, butanol, tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, methyl acetate, ethyl acetate, acetic acid. Propyl, methyl propionate, ethyl propionate, 1,4-dioxane, benzene, toluene, xylene, formic acid, acetic acid, propionic acid, diethylamine, triethylamine, tripropylamine, ethanolamine, n-hexane, n-octane,
Examples thereof include petroleum ether, but preferably water, methanol, ethanol, n-propanol, i-propanol, tetrahydrofuran, 1,2-dimethoxyethane, methyl acetate, ethyl acetate, propyl acetate, methyl propionate, propionic acid. Ethyl, formic acid, acetic acid, triethylamine, toluene, more preferably water,
Methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,2-dimethoxyethane, triethylamine,
It is toluene.

When the solvent is used, the amount used is not limited, but usually 0.5 to 100 volume per 1 weight of the compound (I),
Preferably 0.5 to 50 volumes are used, more preferably 1 to 20 volumes. The solvent may be used alone or as a mixture of two or more kinds.

The order of adding the reducing agent amine and the organic acid is not limited, and the amine may be added first or the organic acid may be added first. That is, an organic acid may be added to a mixed suspension of the compound (I), the catalyst and the amine and, if necessary, the solvent, or a mixed suspension of the compound (I), the catalyst and the organic acid and, if necessary, the solvent. Amine may be added to the liquid

The reaction temperature is not particularly limited and is usually 0 ° C.
~ Performed at the reflux temperature of the amine or solvent. The reaction time is about 1 minute to 48 hours, but it is usually completed in 30 minutes to 12 hours.

When hydrogen gas is used as the reducing agent,
Usually, it can be carried out under the conditions for catalytic reduction in an organic synthesis reaction, that is, under the conditions of atmospheric pressure (atmospheric pressure) to 150 kg / cm ² . In this reaction, it is preferable to use a solvent, and the type, amount of use, reaction temperature and time are the same as in the case of using amine / organic acid as the reducing agent.

When sodium borohydride / cupric chloride is used as the reducing agent, the amount of sodium borohydride used is not limited, but it is usually 1 to 1 with respect to the compound (I).
It is 100 equivalents, preferably 2 to 80 equivalents, and more preferably 5 to 50 equivalents. The amount of cupric chloride used is usually 1 to 50 equivalents, preferably 2 to 30 equivalents, and more preferably 5 to 20 equivalents, relative to compound (I). It is preferable to use a solvent also in this reaction,
The type, the amount used and the reaction temperature / time are the same as in the case of using the amine / organic acid as the reducing agent.

The amount of sodium hypophosphite used as a reducing agent is not limited, but is usually 1 to 100 equivalents, preferably 2 to 50 equivalents, relative to compound (I).
More preferably, it is 5 to 20 equivalents. It is preferable to use a solvent also in this reaction, and the type, the amount to be used and the reaction temperature / time are the same as those in the case of using the amine / organic acid as the reducing agent.

When iron and acetic acid are used as reducing agents, the amount of each is not limited, but usually the amount of iron used is 1 to 100 equivalents, preferably 5 to 75 equivalents, relative to compound (I). , More preferably 10 to 50 equivalents. Also, the amount of acetic acid is usually 1 to 500 equivalents relative to compound (I),
It is preferably 10 to 300 equivalents, more preferably 50 to 2 equivalents.
It is 00 equivalent. A solvent may or may not be used in this reaction, but when a solvent is used, the type, amount used and reaction temperature / time are the same as those in the case of using an amine / organic acid as the reducing agent. is there.

Steps 4 and 5 In Step 4, 2- [N- (biphenyl-4-yl) methyl] alkylamido-3-nitropyridine derivative (I)
Further, in Step 5, all of the 2-alkylamido-5-halogen-3-nitropyridine derivative (III) is a step of selectively reducing only the 5-halogen atom on the pyridine nucleus and performing hydrogen substitution. In these steps, the Pd-C catalyst and the amine / organic acid described in the explanation of step 3 can be used as the combination of the catalyst and the reducing agent, and the reaction time can be the same under the same conditions as the solvent and the reaction temperature. Is usually
It is 5 minutes to 7 hours, preferably 30 minutes to 6 hours, and more preferably 1 to 5 hours. When step 4 is carried out, 2- [N- (biphenyl-4-yl) methyl] alkylamido-3-nitropyridine derivative (VIII) is obtained,
Performing step 5 gives the 2-alkylamido-3-nitropyridine derivative (IX).

Step 6 In this Step, 2-alkylamido-3-nitropyridine derivative (IX) having a hydrogen atom at the 5-position of the pyridine nucleus obtained in Step 5 is N-alkylated to give 2- [N- (Biphenyl-
This is a step of producing 4-yl) methyl] alkylamido-3-nitropyridine derivative (VIII), and can be carried out in the same manner as in step 2.

Step 7 In this step, a 2- [N- (biphenyl-4-yl) methyl] alkylamido-3-nitropyridine derivative (VII obtained in step 4 or step 6 and having a hydrogen atom at the 5-position is used.
I) was cyclized under reducing conditions to give 2-alkyl-3- (biphenyl-4-yl) methyl-3H-imidazo [4,5-
b] A step of producing a pyridine derivative (II).

In this step, reduction / cyclization can be carried out depending on the combination of the catalyst and the reducing agent described in the explanation of step 3 and the reaction conditions. Further, the following reducing agents can be used for reduction / cyclization by a conventional method. a) Iron / acetic acid b) Iron / hydrochloric acid

Step 8 In this step, 2- [N- (biphenyl-4-yl) methyl] alkylamido-3-nitropyridine derivative (I) is reduced and isomerized with activated carbon, hydrazine and ferric chloride to obtain 2 In this step, it is a [-N- (biphenyl-4-yl) methyl] amino-3-alkylamidopyridine derivative (VI). The amount of activated carbon, hydrazine, and ferric chloride used is not limited, but the activated carbon is usually 1 to 50% by weight, preferably 3 to 40% by weight, more preferably 5 to 5% by weight of the compound (I).
Using 30% weight, hydrazine is usually relative to compound (I)
1 to 50 equivalents, preferably 1.5 to 20 equivalents, more preferably 2 to 10 equivalents, ferric chloride is usually 1 to 50 equivalents to the compound (I), preferably 1.5 to 20 equivalents. , And more preferably 2 to 10 equivalents. It is preferable to use a solvent in this step, and the type of the solvent used and the reaction temperature are the same as those in the case of using the amine and the organic acid in step 3.
The reaction time is usually within 48 hours.

Step 9 In this step, 2- [N- (biphenyl-4-yl) methyl] amino-3-alkylamidopyridine derivative (VI) obtained in Step 8 was cyclized under acidic conditions to give 2- Alkyl-
This is a step of producing a 3- (biphenyl-4-yl) methyl-3H-imidazo [4,5-b] pyridine derivative.
This reaction is not limited as long as it is in the presence of an acid usually used in an organic synthesis reaction, and specifically, for example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, perchloric acid, phosphoric acid, The reaction is carried out under acidic conditions using an inorganic acid such as polyphosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid or the like.

Also in this step, it is preferable to use a solvent. Specific examples of the solvent include tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, methyl acetate, ethyl acetate, propyl acetate, methyl propionate, ethyl propionate, 1,4-dioxane, benzene, toluene, Examples thereof include xylene, formic acid, acetic acid, propionic acid, n-hexane, n-octane and petroleum ether, and preferably tetrahydrofuran, 1,2-dimethoxyethane, formic acid, acetic acid, propionic acid, benzene, toluene,
Xylene, more preferably formic acid, acetic acid, benzene, toluene and xylene. Although the amount of the solvent used is not limited, it is usually 0.5 to 1 per 1 weight of the compound (VI).
00 volume, preferably 0.5-50 volume, more preferably 1-
Use 20 volumes. The solvent may be used alone or as a mixture of two or more kinds.

Further, the reaction temperature is not particularly limited and is usually 0.
C. to the reflux temperature of the amine or solvent. Further, in this step, the reaction is accelerated by adding a dehydrating agent such as molecular sieves or by forming an azeotropic mixture to remove water out of the system. In that case, the reaction time is usually completed within 12 hours.

Step 10 In this step, 2- [N-, in which the 5-position is substituted with a halogen atom,
(Biphenyl-4-yl) methyl] alkylamido-3
This is a step of reducing / cyclizing the nitropyridine derivative (I) while leaving a halogen atom. In this step, reduction / cyclization is carried out by a conventional method using iron / acetic acid or iron / hydrochloric acid.

Step 11 In this Step, in the compound obtained in Step 10, 2-alkyl-3- (biphenyl-4-yl) methyl-6-halogen-3H-imidazo substituted at the 6-position with a halogen atom is used. [4,5-b] Pyridine derivative (VII) is reduced / dehalogenated to give the desired 2-alkyl-3- (biphenyl-4-yl) methyl-3H-imidazo [4,5-
b] A step of obtaining a pyridine derivative (II). This step can be performed in the same manner as step 3.

Step 12 In this step, the 2- [N- (biphenyl-
4-yl) methyl] amino-3-alkylamido pyridine derivative (VI) is reduced and dehalogenated to give the desired 2
-Alkyl-3- (biphenyl-4-yl) methyl-3
In this step, the H-imidazo [4,5-b] pyridine derivative (II) is obtained. This step can be performed in the same manner as step 3.

Step 13 The imidazopyridine derivative useful as an angiotensin II receptor antagonist disclosed in JP-A-3-95181 and JP-A-3-236377 is 2-cyclopropyl-3- (2 '-Carboxybiphenyl-4-yl) methyl-7-methyl-3H-imidazo [4,5-b] pyridine and the like, which are compounds having a carboxy group. In order to obtain these compounds, 2-prepared by the method of the present invention
2-Alkyl-3- (biphenyl-4-yl) methyl such as cyclopropyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-7-methyl-3H-imidazo [4,5-b] pyridine -3H-imidazo [4,5
-B] It can be produced by hydrolyzing the ester group or oxazoline group of the pyridine derivative (II) by a conventional method. Among these imidazopyridine derivatives having a carboxy group, a compound having a 2-cyclopropyl group is particularly excellent in angiotensin II receptor antagonistic activity, and is highly useful as an antihypertensive agent or a therapeutic agent for vascular lesions. 2-alkyl-3- (biphenyl-) according to the present invention
The method for producing 4-yl) methyl-3H-imidazo [4,5-b] pyridine derivative (II) can produce a precursor of such angiotensin II receptor antagonist.

Next, the 2-alkylamido-3-nitropyridine derivative (X) represented by the following general formula is a novel compound, and is 2-alkyl-3- (biphenyl-4-yl) methyl-3H-imidazo. [4,5-b] pyridine derivative (I
It is useful as an intermediate in the production of I).

[0086]

[Chemical 30]

In the formula, R ¹ , R ² and R ³ have the same meanings as described above. R ⁶ is a hydrogen atom or a group represented by the following general formula

[0088]

[Chemical 31]

(In the formula, R ⁷ is a group represented by the following general formula:

[0090]

[Chemical 32]

[Wherein R ⁸ is a lower alkyl group, a cycloalkyl group, an alkoxyalkyl group, a thioalkoxyalkyl group, a cycloether group, an aryl group, an aralkyl group,
It means an alkenyl group, an alkynyl group or a trialkylsilyl group. } Or a group represented by the following general formula

[0092]

[Chemical 33]

Means ) Means. Specific examples of R ⁸ include the same groups as R ⁵ in the above 2- [N- (2′-biphenyl-4-yl) methyl] alkylamido-3-nitropyridine derivative (I). You can More specifically, for example, the following compounds can be mentioned, but 2-alkylamide-
The 3-nitropyridine derivative (X) is not limited to these.

(1) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] cyclopropanecarboxamido-4-methyl-3-nitropyridine (2) 2- [N- (2'-methoxy Carbonylbiphenyl-4-yl) methyl] cyclopropanecarboxamide-
4,6-Dimethyl-3-nitropyridine (3) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] cyclopropanecarboxamide-
5-Bromo-4-methyl-3-nitropyridine (4) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] cyclopropanecarboxamide-
5-chloro-4-methyl-3-nitropyridine (5) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] cyclopropanecarboxamide-
5-Bromo-4,6-dimethyl-3-nitropyridine (6) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] cyclopropanecarboxamide-
5-Chloro-4,6-dimethyl-3-nitropyridine (7) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] butyrylamino-4-methyl-3
-Nitropyridine (8) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] butyrylamino-4,6-dimethyl-3-nitropyridine (9) 2- [N- (2'-methoxy Carbonylbiphenyl-4-yl) methyl] butyrylamino-5-bromo-4
-Methyl-3-nitropyridine (10) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] butyrylamino-5-bromo-
4,6-Dimethyl-3-nitropyridine (11) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] valerylamino-4-methyl-3
-Nitropyridine (12) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] valerylamino-4,6-dimethyl-3-nitropyridine (13) 2- [N- (2'-methoxy Carbonylbiphenyl-4-yl) methyl] valerylamino-5-bromo-4
-Methyl-3-nitropyridine (14) 2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] valerylamino-5-bromo-
4,6-Dimethyl-3-nitropyridine (15) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl]
Cyclopropanecarboxamido-4-methyl-3-nitropyridine (16) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl]
Cyclopropane carboxamide-4,6-dimethyl-3
-Nitropyridine (17) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl]
Cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine (18) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl ]
Cyclopropanecarboxamido-5-chloro-4-methyl-3-nitropyridine (19) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl ]
Cyclopropane carboxamide-5-bromo-4,6-
Dimethyl-3-nitropyridine (20) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl]
Cyclopropane carboxamide-5-chloro-4,6-
Dimethyl-3-nitropyridine (21) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl]
Butyrylamino-4-methyl-3-nitropyridine (22) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl]
Butyrylamino-4,6-dimethyl-3-nitropyridine (23) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl]
Butyrylamino-5-bromo-4-methyl-3-nitropyridine (24) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl]
Butyrylamino-5-bromo-4,6-dimethyl-3-
Nitropyridine (25) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl]
Valerylamino-4-methyl-3-nitropyridine (26) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl]
Valerylamino-4,6-dimethyl-3-nitropyridine (27) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl]
Valerylamino-5-bromo-4-methyl-3-nitropyridine (28) 2- [N- {2 '-(4 ", 4" -dimethyloxazolin-2 "-yl) biphenyl-4-yl} methyl]
Valerylamino-5-bromo-4,6-dimethyl-3-
Nitropyridine (29) 2-Cyclopropanecarboxamide-4-methyl-
3-Nitropyridine (30) 2-Cyclopropanecarboxamide-4,6-dimethyl-3-nitropyridine (31) 2-Cyclopropanecarboxamide-5-bromo-
4-Methyl-3-nitropyridine (32) 2-cyclopropanecarboxamide-5-chloro-
4-Methyl-3-nitropyridine (33) 2-cyclopropanecarboxamide-5-bromo-
4,6-Dimethyl-3-nitropyridine (34) 2-Cyclopropanecarboxamide-5-chloro-
4,6-Dimethyl-3-nitropyridine (35) 2-butyrylamino-4-methyl-3-nitropyridine (36) 2-butyrylamino-4,6-dimethyl-3-nitropyridine (37) 2-butyrylamino-5 -Bromo-4-methyl-3
-Nitropyridine (38) 2-butyrylamino-5-bromo-4,6-dimethyl-3-nitropyridine (39) 2-valerylamino-4-methyl-3-nitropyridine (40) 2-valerylamino-4,6- Dimethyl-3-nitropyridine (41) 2-valerylamino-5-bromo-4-methyl-3
-Nitropyridine (42) 2-valerylamino-5-bromo-4,6-dimethyl-3-nitropyridine

In addition, 2- [N- represented by the following general formula
(Biphenyl-4-yl) methyl] amino-3-alkylamidopyridine derivative (VI) is also a novel compound,
Alkyl-3- (biphenyl-4-yl) methyl-3H
-Useful as an intermediate in the production of imidazo [4,5-b] pyridine derivative (II).

[0096]

[Chemical 34]

In the formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above. More specifically, for example, the following compounds can be mentioned, but the 2- [N- (biphenyl-4-yl) methyl] amino-3-alkylamidopyridine derivative (VI) according to the present invention is limited to these. Not done.

(1) 3-Cyclopropanecarboxamide-
2- [N- (2'-methoxycarbonylbiphenyl-4
-Yl) methyl] amino-4-methylpyridine (2) 3-cyclopropanecarboxamide-2- [N-
(2'-Methoxycarbonylbiphenyl-4-yl) methyl] amino-4,6-dimethylpyridine (3) 3-cyclopropanecarboxamide-2- [N-
(2′-Methoxycarbonylbiphenyl-4-yl) methyl] amino-5-bromo-4-methylpyridine (4) 3-cyclopropanecarboxamide-2- [N-
(2'-Methoxycarbonylbiphenyl-4-yl) methyl] amino-5-chloro-4-methylpyridine (5) 3-cyclopropanecarboxamide-2- [N-
(2'-Methoxycarbonylbiphenyl-4-yl) methyl] amino-5-bromo-4,6-dimethylpyridine (6) 3-cyclopropanecarboxamide-2- [N-
(2'-Methoxycarbonylbiphenyl-4-yl) methyl] amino-5-chloro-4,6-dimethylpyridine (7) 3-butyrylamino-2- [N- (2'-methoxycarbonylbiphenyl-4-yl) Methyl] amino-4
-Methylpyridine (8) 3-butyrylamino-2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] amino-
4,6-Dimethylpyridine (9) 3-butyrylamino-2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] amino-5
-Bromo-4-methylpyridine (10) 3-butyrylamino-2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] amino-5
-Bromo-4,6-dimethylpyridine (11) 3-valerylamino-2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] amino-4
-Methylpyridine (12) 3-valerylamino-2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] amino-
4,6-Dimethylpyridine (13) 3-valerylamino-2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] amino-5
-Bromo-4-methylpyridine (14) 3-valerylamino-2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] amino-5
-Bromo-4,6-dimethylpyridine (15) 3-cyclopropanecarboxamide-2- [N-
{2 '-(4 ", 4" -dimethyloxazoline-2 "-
Iyl) biphenyl-4-yl} methyl] amino-4-methyl-pyridine (16) 3-cyclopropanecarboxamide-2- [N-
{2 '-(4 ", 4" -dimethyloxazoline-2 "-
Il) biphenyl-4-yl} methyl] amino-4,6
-Dimethylpyridine (17) 3-Cyclopropanecarboxamide-2- [N-
{2 '-(4 ", 4" -dimethyloxazoline-2 "-
Iyl) biphenyl-4-yl} methyl] amino-5-bromo-4-methylpyridine (18) 3-cyclopropanecarboxamide-2- [N-
{2 '-(4 ", 4" -dimethyloxazoline-2 "-
Iyl) biphenyl-4-yl} methyl] amino-5-chloro-4-methylpyridine (19) 3-cyclopropanecarboxamide-2- [N-
{2 '-(4 ", 4" -dimethyloxazoline-2 "-
Il) biphenyl-4-yl} methyl] amino-5-bromo-4,6-dimethylpyridine (20) 3-cyclopropanecarboxamide-2- [N-
{2 '-(4 ", 4" -dimethyloxazoline-2 "-
Iyl) biphenyl-4-yl} methyl] amino-5-chloro-4,6-dimethylpyridine (21) 3-butyrylamino-2- [N- {2 '-(4 ",
4 "-dimethyloxazoline-2" -yl) biphenyl-4-yl} methyl] amino-4-methylpyridine (22) 3-butyrylamino-2- [N- {2 '-(4 ",
4 "-dimethyloxazolin-2" -yl) biphenyl-4-yl} methyl] amino-4,6-dimethylpyridine (23) 3-butyrylamino-2- [N- {2 '-(4 ",
4 "-dimethyloxazoline-2" -yl) biphenyl-4-yl} methyl] amino-5-bromo-4-methylpyridine (24) 3-butyrylamino-2- [N- {2 '-(4 ",
4 "-dimethyloxazoline-2" -yl) biphenyl-4-yl} methyl] amino-5-bromo-4,6-dimethylpyridine (25) 3-valerylamino-2- [N- {2 '-(4 " ，
4 "-dimethyloxazolin-2" -yl) biphenyl-4-yl} methyl] amino-4-methylpyridine (26) 3-valerylamino-2- [N- {2 '-(4 ",
4 "-dimethyloxazolin-2" -yl) biphenyl-4-yl} methyl] amino-4,6-dimethylpyridine (27) 3-valerylamino-2- [N- {2 '-(4 ",
4 "-dimethyloxazoline-2" -yl) biphenyl-4-yl} methyl] amino-5-bromo-4-methylpyridine (28) 3-valerylamino-2- [N- {2 '-(4 ",
4 "-dimethyloxazolin-2" -yl) biphenyl-4-yl} methyl] amino-5-bromo-4,6-dimethylpyridine

Next, prior to the examples, examples of production of raw material intermediates necessary for carrying out the present invention will be described.

Production Example 1 4-Bromobenzyl-methoxy
Synthesis of methyl ether

[0101]

[Chemical 35]

4-bromobenzyl alcohol 10.0 g (53.
5 mmol) was dissolved in tetrahydrofuran (200 ml). Under ice-cooling, 6.6 g (58.8 mmol) of potassium t-butoxide was added thereto and stirred for 1 hour, and subsequently 5.2 g (64.6 mmol) of chloromethyl methyl ether was added dropwise. Then another 12 at room temperature
After stirring for an hour, the reaction solution was added to a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. It was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 11.0 g of the title compound as an oil. (Yield 89%)

¹ H-NMR (90 MHz, CDCl ₃ ); δ (ppm) 3.40 (3
H, s), 4.52 (2H, s), 4.66 (2H, s), 7.16 (2H, d, J = 8.0Hz), 7.40
(2H, d, J = 8.0Hz)

Production Example 2 4-Bromobenzyl-tetrahi
Synthesis of doropyranyl ether

[0105]

[Chemical 36]

4-bromobenzyl alcohol 10.0 g (53.
5 mmol), 3,4-dihydro-2H-pyran 4.95 g (58.8 m
mol) was dissolved in methylene chloride (50 ml). Under ice cooling, here
100 mg of p-toluenesulfonic acid monohydrate was added and stirred for 3 hours. The reaction solution was added to an aqueous sodium hydrogen carbonate solution and extracted with chloroform. It was washed with water, dried, and concentrated under reduced pressure. The residue was distilled under reduced pressure (160 ° C / 1mmHg) to give 12.0 of the title compound as an oil.
got g. (83% yield)

¹ H-NMR (90 MHz, CDCl ₃ ); δ (ppm) 1.40 ~
2.10 (6H, m), 3.38 ~ 3.70 (1H, m), 3.70 ~ 4.02 (1H, m), 4.41
(1H, d, J = 13.0Hz), 4.64 (1H, s), 4.70 (1H, d, J = 13.0Hz), 7.1
8 (2H, d, J = 8.0Hz), 7.44 (2H, d, J = 8.0Hz)

Production Example 3 4,4-dimethyl-2- (4 '
-Methylbiphenyl-2-yl) oxazoline synthesis

[0109]

[Chemical 37]

Tetrahydrofuran (200 ml) was added to 2.5 g (103 mmol) of magnesium pieces, and a small amount of dibromoethane was added with stirring. After confirming foaming, 13 ml of 4-bromotoluene
(106 mmol) was added dropwise. After confirming the dissolution of magnesium,
Stirring was continued for another hour at room temperature. Add this reaction mixture to 4,4
A solution of 10.0 g (48.7 mmol) of dimethyl-2- (2′-methoxyphenyl) oxazoline in tetrahydrofuran (100 ml) was added dropwise, and stirring was continued for 12 hours thereafter. The reaction solution was poured into a saturated aqueous solution of ammonium chloride and extracted with chloroform. It was washed with water, dried, and concentrated under reduced pressure. Silica gel column chromatography of the residue (n-hexane: ethyl acetate)
After that, 11.0 g of crystals of the title compound were obtained. (Yield 85
%)

Melting point: 56-59 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ); δ (ppm) 1.30 (6 H, s), 2.38 (3
H, s), 3.80 (2H, s), 7.00 to 7.50 (7H, m), 7.70 (1H, dd, J = 7.5,
1.5Hz) FAB-MS; 266 (MH ⁺ )

Production Example 4 4,4-Dimethyl-2- (4 '
-Methoxymethoxymethylbiphenyl-2-yl) oxy
Sazoline synthesis

[0113]

[Chemical 38]

Tetrahydrofuran (15 ml) was added to 408 mg (16.8 mmol) of magnesium pieces, and a small amount of dibromoethane was added with stirring. After confirming foaming, a solution of 3.23 g (14.0 mmol) of 4-bromobenzyl-methoxymethyl ether in tetrahydrofuran (15 ml) was added dropwise. After confirming dissolution of magnesium, stirring was continued at room temperature for another hour. Then 4,4
A solution of 2.10 g (10.2 mmol) of -dimethyl-2- (2'-methoxyphenyl) oxazoline in tetrahydrofuran (15 ml) was added dropwise and stirred for 12 hours. The reaction solution was poured into a saturated aqueous solution of ammonium chloride and extracted with chloroform. It was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to give 3.20 g of the title compound as an oil. (Yield 96%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.30 (6
H, s), 3.45 (3H, s), 3.80 (2H, s), 4.64 (2H, s), 4.74 (2H, s),
7.34 ~ 7.40 (6H, m), 7.48 (1H, ddd, J = 8.5, 8.0, 1.5Hz), 7.
73 (1H, dd, J = 8.0, 1.5Hz) FAB-MS; 326 (MH ⁺ )

Production Example 5 4,4-dimethyl-2- (4 '
-Tetrahydropyranyloxymethylbiphenyl-2-
Il) Synthesis of oxazoline

[0117]

[Chemical Formula 39]

Tetrahydrofuran (15 ml) was added to 1.2 g (49.4 mmol) of magnesium pieces, and a small amount of dibromoethane was added with stirring. After confirming foaming, a solution of 4-bromobenzyl-tetrahydropyranyl ether 11.0 g (40.6 mmol) in tetrahydrofuran (15 ml) was added dropwise. After confirming dissolution of magnesium, stirring was continued at room temperature for another hour. Then 4,
A solution of 7.0 g (34.1 mmol) of 4-dimethyl-2- (2'-methoxyphenyl) oxazoline in tetrahydrofuran (5 ml) was added dropwise, and the mixture was stirred for 12 hours. The reaction solution was poured into a saturated aqueous solution of ammonium chloride and extracted with chloroform. It was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to give 6.61 g of the title compound as an oil. (53% yield)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.29 (6
H, s), 1.50 to 1.94 (6H, m), 3.52 to 3.59 (1H, m), 3.80 (2H, s),
3.91 to 3.97 (1H, m), 4.55 (1H, d, J = 12.3Hz), 4.73 (1H, t, J =
3.7Hz), 4.84 (1H, d, J = 12.3Hz), 7.38 (4H, s), 7.34-7.40 (2
H, m), 7.48 (1H, ddd, J = 8.0, 7.5,1.5Hz), 7.72 (1H, ddd, J =
8.0, 1.5, 1.0Hz) FAB-MS; 366 (MH ⁺ )

Production Example 6 4,4-dimethyl-2- (4 '
-Hydroxymethylbiphenyl-2-yl) oxazoli
Synthesis

[0121]

[Chemical 40]

4,4-Dimethyl-2- (4'-methoxymethoxymethylbiphenyl-2-yl) oxazoline
2.62 g (8.05 mmol) was dissolved in methanol (20 ml) and 6N-hydrochloric acid was added.
(10 ml) was added and the mixture was stirred at 40 ° C for 2 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. It was washed with water, dried, and concentrated under reduced pressure. Silica gel column chromatography of the residue (n-hexane: ethyl acetate)
The crystals were purified by to give 2.20 g of crystals of the title compound. (Yield 97
%)

Melting point: 97-100 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.30 (6 H, s), 1.75 (1
H, br-s), 3.80 (2H, s), 4.75 (2H, s), 7.40 (4H, s), 7.35 to 7.4
2 (2H, m), 7.48 (1H, ddd, J = 8.0, 7.5, 1.3Hz), 7.73 (1H, dd,
J = 8.1, 1.3Hz) EI-MS; 280 (MH ⁺ )

Production Example 7 4,4-dimethyl-2- (4 '
-Hydroxymethylbiphenyl-2-yl) oxazoli
Synthesis of 4,4-dimethyl-2- (4'-tetrahydropyranyloxymethylbiphenyl-2-yl) oxazoline 4.0
g (10.9 mmol) was dissolved in methanol (50 ml) and 6N-hydrochloric acid (15 m
l) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform.
It was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to give 3.0 g of the title compound. (Yield 98%)

Production Example 8 4,4-Dimethyl-2- (4 '
-Carboxybiphenyl-2-yl) oxazoline
Success

[0126]

[Chemical 41]

2,4-Dimethyl-2- (4'-methylbiphenyl-2-yl) oxazoline (20.0 g, 75.4 mmol) was dissolved in pyridine (75 ml) and water (150 ml) and heated under reflux to give permanganate. 71.4 g (452 mmol) of potassium was added little by little,
After the addition, the mixture was refluxed for 4 hours. The reaction solution was cooled and the insoluble material was filtered off. After washing the residue with hot water, the filtrates were combined and concentrated under reduced pressure. Concentrated hydrochloric acid was added to the residue and the precipitated crystals were collected by filtration,
20.4 g of crystals of the title compound were obtained. (Yield 92%)

Melting point: 190-193 ° C. ¹ H-NMR (600 MHz, CDCl ₃ ); δ (ppm) 1.16 (6 H, s), 3.79 (2
H, s), 7.43 to 7.48 (4H, m), 7.49 (1H, dt, J = 7.5, 1.5Hz), 7.5
8 (1H, dd, J = 7.5,1.0Hz), 7.96 (2H, dd, J = 8.6,1.9Hz), 12.9
0 (1H, br) FAB-MS; 296 (MH ⁺ )

Production Example 9 4,4-dimethyl-2- (4 '
-Hydroxymethylbiphenyl-2-yl) oxazoli
Emissions of lithium aluminum hydride 1.28g of (33.7 mmol) was suspended in tetrahydrofuran (20ml). 4,4 at room temperature
-Dimethyl-2- (4'-carboxybiphenyl-2-
5.0 g (16.9 mmol) of (yl) oxazoline was slowly added, and the mixture was stirred for 2 hours after the addition. After cooling the reaction mixture with ice, water (100 m
l) was added for hydrolysis, and the mixture was extracted with chloroform. It was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to obtain 4.2 g of the title compound. (88% yield)

Production Example 10 4,4-Dimethyl-2-
(4'-methoxycarbonylbiphenyl-2-yl) o
Synthesis of xazoline

[0131]

[Chemical 42]

10.0 g (33.8 mmo) of 4,4-dimethyl-2- (4'-carboxybiphenyl-2-yl) oxazoline
l) was dissolved in methylene chloride (200 ml). Thionyl chloride (4.8 g, 40.3 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, methanol (100 ml) was added to the residue, and the mixture was stirred for 3 hours. After the solvent was distilled off under reduced pressure, methylene chloride and saturated aqueous sodium hydrogen carbonate solution were added to the residue for partitioning. It was washed with water, dried, and concentrated under reduced pressure. Silica gel column chromatography of the residue (ethyl acetate: n-hexane system)
The product was purified by the above method to give 9.53 g of the title compound as an oil. (Yield 91
%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.26 (6
H, s), 3.77 (2H, s), 3.92 (3H, s), 7.28 to 7.56 (5H, m), 7.75 (1
H, d, J = 8.5Hz), 8.03 (2H, d, J = 7.5Hz) FAB-MS; 310 (MH ⁺ )

Production Example 11 4,4-dimethyl-2-
(4'-Hydroxymethylbiphenyl-2-yl) oxy
Synthesis of Sazoline 2.0 g (6.46 mmol) of 4,4-dimethyl-2- (4′-methoxycarbonylbiphenyl-2-yl) oxazoline was dissolved in tetrahydrofuran (20 ml). Under ice cooling, 0.49 g (12.9 mmol) of lithium aluminum hydride was slowly added thereto, and the mixture was stirred as it was for 2 hours. Water (50 ml) was added for hydrolysis, followed by extraction with chloroform. It was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to give 1.69 g of the title compound. (Yield 93%)

Production Example 12 2- (4'-hydroxymethyi)
Synthesis of ruphenyl) benzoic acid

[0136]

[Chemical 43]

2.0 g of 4,4-dimethyl-2- (4'-hydroxymethylbiphenyl-2-yl) oxazoline (7.
11 mmol) in methylene chloride (10 ml) and methyl iodide
3.0 g (21.1 mmol) was added and the mixture was stirred for 12 hours. The reaction mixture was concentrated to dryness, methanol (20 ml) and 20% aqueous sodium hydroxide solution (20 ml) were added, and the mixture was heated under reflux for 13 hr. After cooling to room temperature and adjusting the pH to 6 with hydrochloric acid, the mixture was extracted with chloroform. It was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol system) to give crystals of the title compound (1.24 g). (yield
77%)

Melting point: 140-142 ° C. ¹ H-NMR (90 MHz, CDCl ₃ ); δ (ppm) 4.70 (2H, s), 5.25 (1H,
br-s), 7.20-7.62 (7H, m), 7.90 (1H, dd, J = 7.6, 1.5Hz) FAB-MS; 228 (M ⁺ )

Production Example 13 2- (4'-hydroxymethyi)
Synthesis of ruphenyl) benzoic acid 4,4-Dimethyl-2- (4'-hydroxymethylbiphenyl-2-yl) oxazoline 2.0 g (7.11 mmol) was dissolved in ethanol (30 ml), and 2N-hydrochloric acid (10 ml) was added. And refluxed for 3 hours. The reaction mixture was cooled and concentrated, saturated aqueous sodium hydrogen carbonate solution (100 ml) was added, and the mixture was extracted with chloroform. The organic layer was washed with water, dried, and concentrated under reduced pressure. 20% on the residue-
Aqueous sodium hydroxide solution (20 ml) and ethanol (20 ml) were added, and the mixture was heated back for 8 hours. The reaction solution was cooled to room temperature, adjusted to pH 6 with hydrochloric acid and then extracted with chloroform. The organic layer was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol system) to give the title compound (1.31 g). (Yield 81%)

Production Example 14 2- (4'-hydroxymethyi)
Synthesis of ruphenyl) benzoic acid 4,4-dimethyl-2- (4'-hydroxymethylbiphenyl-2-yl) oxazoline 2.0 g (7.11 mmol) in water
(6 ml) and sulfuric acid (3.6 g) were added, and the mixture was heated under reflux for 30 hours. The reaction solution was cooled, neutralized with 10% aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol system) to give the title compound 1.0
Got 5g. (Yield 65%)

Production Example 15 2- (4'-hydroxymethyi)
Synthesis of methyl (phenyl) benzoate

[0142]

[Chemical 44]

2- (4'-hydroxymethylphenyl)
Benzoic acid (4.0 g, 17.5 mmol) was dissolved in methanol (50 ml), sulfuric acid (1 ml) was added, and the mixture was heated under reflux for 8 hours. After concentration under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to give 3.8 g of the title compound as an oil. (Yield 89%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.60 (1
H, br-s), 3.64 (3H, s), 4.72 (2H, s), 7.29 (2H, d, J = 8.0Hz),
7.33 (1H, dd, J = 7.7, 1.4Hz), 7.38 (1H, td, J = 7.7, 1.4Hz),
7.39 (2H, d, J = 8.0Hz), 7.51 (1H, td, J = 7.7, 1.4Hz), 7.81 (1
H, dd, J = 7.7, 1.4Hz) FAB-MS; 242 (M ⁺ )

Production Example 16 2- (4′-chloromethylphenyl)
Synthesis of methyl) benzoate

[0146]

[Chemical formula 45]

2- (4'-hydroxymethylphenyl)
A solution of 5.0 g (20.6 mmol) of methyl benzoate in methylene chloride (50
(ml) was added dropwise with thionyl chloride (4.8 g, 40.3 mmol) under ice cooling. After the dropping was completed, the temperature was returned to room temperature and the mixture was stirred for 4.5 hours. A saturated aqueous sodium hydrogencarbonate solution (150 ml) was added dropwise to the reaction solution, and the mixture was extracted twice with ethyl acetate (150 ml, 100 ml), and the organic layers were washed together with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give an oily residue (5.8 g). This crude product was subjected to silica gel calm chromatography (n-
Hexane: ethyl acetate system) and the title compound 4.9g
Got (Yield: 91%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 3.65 (3
H, s), 4.64 (2H, s), 7.30 (2H, d, J = 7.8Hz), 7.36 (1H, dd, J = 7.
8, 1.5Hz), 7.40 to 7.44 (3H, m), 7.53 (1H, td, J = 7.8, 1.4H
z), 7.85 (1H, d, J = 8.3Hz) FAB-MS; 261 (MH ⁺ )

Production Example 17 2- (4'-bromomethylphenyl)
Synthesis of methyl) benzoate

[0150]

[Chemical formula 46]

2- (4'-hydroxymethylphenyl)
10.0 g (41 mmol) of methyl benzoate was dissolved in 7.9 g of pyridine and n-hexane (100 ml). Under ice cooling, phosphorus tribromide here
8.3 g (31 mmol) was added dropwise and the mixture was stirred for 2 hours as it was. The reaction solution was added to an aqueous sodium hydrogen carbonate solution and extracted with n-hexane. The organic layer was washed with water, dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to give the title compound (9.5 g). (Yield 75
%)

Melting point: 50-51 ° C. ¹ H-NMR (90 MHz, CDCl 3); δ (ppm) 3.62 (3 H, s), 5.01 (2 H,
s), 7.12-7.60 (7H, m), 7.68-7.85 (1H, m) FAB-MS; 305,307 (MH ⁺ )

Production Example 18 2- (4'-bromomethylphenyl)
Synthesis of Methyl 2- (4'-methylphenyl) benzoate 2.0g (8.8
mmol), 1.6 g (9.0 mmol) of N-bromosuccinimide and α,
α'-Azobis (isobutyronitrile) [alias; 2,2'-azobis (isobutyronitrile)] 0.05 g of carbon tetrachloride (1
It was dissolved in 10 ml) and heated under reflux for 2 hours. The insoluble material was filtered off and then concentrated under reduced pressure. The residue was recrystallized from n-hexane: isopropyl ether mixed solvent to give 1.6 g of the title compound.
Got (Yield: 59%)

Production Example 19 2- (4'-methanesulfoni)
Synthesis of methyl luoxymethylphenyl) benzoate

[0155]

[Chemical 47]

2- (4'-hydroxymethylphenyl)
10.0 g (41 mmol) of methyl benzoate and triethylamine 8.4
g (83.0 mmol) was dissolved in methylene chloride (150 ml) and cooled under ice,
A solution of 5.7 g (50 mmol) of methanesulfonyl chloride in methylene chloride (25 ml) was added dropwise thereto, and stirring was continued for another hour.
The reaction solution was poured into water and extracted with methylene chloride. The organic layer was washed with water, dried and concentrated under reduced pressure to give the wax-like title compound 1
3.1 g was obtained. (Yield 100%)

Melting point: 43-45 ° C. ¹ H-NMR (90 MHz, CDCl ₃ ); δ (ppm) 2.96 (3 H, s), 3.64 (3 H,
s), 5.25 (2H, s), 7.20 ~ 7.60 (7H, m), 7.72 ~ 7.90 (1H, m)

Production Example 20 2- (4′-p-toluenesulfur)
Synthesis of methyl phenyloxymethylphenyl) benzoate

[0159]

[Chemical 48]

2- (4'-hydroxymethylphenyl)
10.0 g (41 mmol) of methyl benzoate was added to tetrahydrofuran (2
It was dissolved in 00 ml). Under ice cooling, 2.0 g (50 mmol) of 60% -sodium hydride was added thereto, and stirring was continued for 1 hour. here,
A solution of 8.65 g (45.4 mmol) of p-toluenesulfonyl chloride in tetrahydrofuran (50 ml) was added dropwise. Then, the mixture was reacted at room temperature for 2 hours, and further heated under reflux for 4 hours. The reaction solution was cooled and added to a saturated aqueous solution of ammonium chloride. From there it was extracted with chloroform (200 ml). The organic layer was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to give 13.4 g of the waxy title compound. (Yield 82%)

¹ H-NMR (90 MHz, CDCl ₃ ); δ (ppm) 2.44 (3
H, s), 3.60 (3H, s), 5.07 (2H, s), 7.23 (4H, s), 7.34 (2H, d, J =
7.7Hz), 6.96 to 7.60 (3H, m), 7.77 (2H, d, J = 7.7Hz), 7.64 to
7.90 (1H, m)

Production Example 21 4,4-dimethyl-2-
(4'-Chloromethylbiphenyl-2-yl) oxazo
Phosphorus synthesis

[0163]

[Chemical 49]

1.0 g of 4,4-dimethyl-2- (4'-hydroxymethylbiphenyl-2-yl) oxazoline (3.
55 mmol) was dissolved in methylene chloride (15 ml). Under ice-cooling, 0.51 g (4.29 mmol) of thionyl chloride was added dropwise thereto and stirred for 1 hour. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate and extracted with methylene chloride. The crystals were washed with water, dried and concentrated under reduced pressure to give the title compound (1.05 g) as crystals. (Yield 99%)

Melting point; 72-75 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.29 (6 H, s), 3.80 (2
H, s), 4.64 (2H, s), 7.35 to 7.43 (6H, m), 7.62 (1H, td, J = 7.6,
1.5Hz), 7.73 (1H, ddd, J = 7.6, 1.5, 1.0Hz) FAB-MS; 300 (MH ⁺ )

Production Example 22 4,4-Dimethyl-2-
(4'-methanesulfonyloxymethylbiphenyl-2
-Yl) Synthesis of oxazoline

[0167]

[Chemical 50]

2.0 g of 4,4-dimethyl-2- (4'-hydroxymethylbiphenyl-2-yl) oxazoline (7.
1 mmol) and 1.43 g (14.1 mmol) of triethylamine were dissolved in methylene chloride (20 ml), and the solution was added dropwise to 0.98 g (8.6 mmol) of methanesulfonyl chloride methylene chloride (10 ml) under cooling with salt ice. After stirring for 3 hours as it was, the reaction solution was poured into water and extracted with methylene chloride. The extract was washed with water, dried, and concentrated under reduced pressure to give the title compound (2.53 g) as an oil. (Yield 99%)

¹ H-NMR (90 MHz, CDCl ₃ ); δ (ppm) 1.31 (6
H, s), 2.94 (3H, s), 3.80 (2H, s), 6.26 (2H, s), 7.40 (4H, s),
7.14 ~ 7.80 (4H, m)

Production Example 23 4,4-dimethyl-2-
(4'-p-toluenesulfonyloxymethylbiphenyl
Synthesis of (ru-2-yl) oxazoline

[0171]

[Chemical 51]

60% -0.34 g of oily sodium hydride (8.5 mmo
l) was suspended in tetrahydrofuran (20 ml). At room temperature
2.04 g (7.1 mmol) of 4,4-dimethyl-2- (4'-hydroxymethylbiphenyl-2-yl) oxazoline
Tetrahydrofuran solution (30 ml) was added dropwise, and the mixture was stirred at room temperature for another hour. After ice-cooling the reaction solution, a tetrahydrofuran (20 ml) solution of 1.6 g (8.4 mmol) of p-toluenesulfonyl chloride was added dropwise. After stirring for 3 hours as it was, the reaction solution was poured into a saturated aqueous solution of ammonium chloride and extracted with chloroform. It was washed with water, dried, and concentrated under reduced pressure. Silica gel column chromatography of the residue (n-hexane: ethyl acetate)
After purification, 1.7 g of the title compound was obtained as an oil. (Yield 55
%)

¹ H-NMR (90 MHz, CDCl ₃ ); δ (ppm) 1.28 (6
H, s), 2.24 (3H, s), 3.76 (2H, s), 5.07 (2H, s), 7.11 to 7.70 (1
0H, m), 7.78 (2H, d, J = 8Hz) FAB-MS; 436 (MH ⁺ )

Next, examples will be given below for specifically explaining the present invention, but it goes without saying that the present invention is not limited thereto.

[0175]

EXAMPLES Example 1 2-Cyclopropanecarboxamido-5-bu
Synthesis of lomo-4-methyl-3-nitropyridine

[0176]

[Chemical 52]

2-amino-5-bromo-4-methyl-3
A mixture of 10 g (43.1 mmol) of -nitropyridine, 6.3 g of 4-dimethylaminopyridine and xylene (50 ml) was heated at 110 ° C under a nitrogen atmosphere. 5 g (47.4 mmol) of cyclopropanecarbonyl chloride was added dropwise thereto, and the mixture was further stirred at 110 ° C. for 2 hours. The reaction mixture was returned to room temperature, methylene chloride (200 ml) and water (50 ml) were added, and the organic layer was separated. The aqueous layer was further extracted with methylene chloride (50 ml), and the organic layers were combined and washed with water (50 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain crude crystals. Recrystallization from chloroform-ethyl acetate gave 11.4 g of the title compound. (Yield 88%)

Melting point: 204.7 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 0.91 to 0.96 (2 H, m),
1.12 ~ 1.16 (2H, m), 1.59 ~ 1.71 (1H, m), 2.52 (3H, s), 8.21
(1H, br-s), 8.58 (1H, S) FAB-MS; 300,302 (MH ⁺ )

Example 2 2-Cyclopropanecarboxa
Synthesis of mid-4-methyl-3-nitropyridine

[0180]

[Chemical 53]

A mixture of 5.0 g (32.6 mmol) of 2-amino-4-methyl-3-nitropyridine and 5.2 g of pyridine was heated at 110 ° C. under a nitrogen atmosphere. Cyclopropanecarbonyl chloride (3.8 g, 36 mmol) was added dropwise thereto, and the mixture was further stirred at 110 ° C. for 5 hours. The reaction mixture was returned to room temperature and chloroform (50 ml).
And water (50 ml) were added and the organic layer was separated. The aqueous layer was further extracted twice with chloroform (50 ml), the organic layers were combined, and water (2
It was washed with saturated saline (20 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to give the title compound (5.4 g). (Yield 75
%)

Melting point: 179 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 0.89 to 0.94 (2 H, m),
1.11 ~ 1.15 (2H, m), 1.67 ~ 1.73 (1H, m), 2.49 (3H, d, J = 0.6H
z), 7.08 (1H, dd, J = 5.0, 0.6Hz), 8.36 (1H, d, J = 5.0Hz), 8.6
1 (1H, br-s) FAB-MS; 222 (MH ⁺ )

Example 3 2-Cyclopropanecarboxa
Synthesis of mid-4-methyl-3-nitropyridine 5-bromo-2-cyclopropanecarboxamide-4-
Methyl-3-nitropyridine 3.0 g (10.0 mmol), 10% Pd-C
(100 mg), triethylamine 2.9 g (28.6 mmol) in toluene
(60 ml) was added, and the mixture was stirred and heated to reflux. Formic acid 1.9 in this solution
g (41.3 mmol) was added dropwise and stirring was continued for 5 hours. The reaction solution was returned to room temperature, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. Chloroform (100 ml) and water (100 ml) were added to the residue for liquid separation, and the aqueous layer was further extracted once with chloroform (50 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to give 1.6 g of the title compound. (Yield 72%)

Example 4 2- [N- (2'-Methoxyca
Rubonylbiphenyl-4-yl) methyl] cyclopropa
Carboxamide-5-bromo-4-methyl-3-nit
Synthesis of lopyridine

[0185]

[Chemical 54]

0.40 g (3.56 mmol) of potassium t-butoxide
0.95 g (3.17 mmol) of 2-cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine was added to a tetrahydrofuran (15 ml) solution of and was stirred at room temperature for 30 minutes. Next, the solution is heated and refluxed to give 2- (4′-
Chloromethylphenyl) methyl benzoate 0.91g (3.49g)
Tetrahydrofuran solution (10 ml) was added dropwise. After the dropping was completed, the mixture was stirred under reflux for 23 hours. The reaction solution was returned to room temperature and saturated ammonium chloride aqueous solution (30 ml) and ethyl acetate (20 ml) were added for extraction. From the aqueous layer, twice with ethyl acetate (20 ml
X2) Extracted. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 1.25 g of an oily residue. The crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to obtain 1.01 g of the title compound. (Yield; 61%)

¹ H-NMR (600 MHz, CDCl ₃ ); δ (ppm) 0.70 ~
0.85 (2H, br), 1.00 to 1.20 (2H, br), 1.56 (1H, br), 2.43 (3H, br
s), 3.60 (3H, s), 5.00 to 5.40 (2H, br), 7.00 to 7.45 (4H, br),
7.33 (1H, dd, J = 7.7, 1.1Hz), 7.37 (1H, ddd, J = 7.7, 7.7,
1.1Hz), 7.49 (1H, ddd, J = 7.7, 7.7, 1.1Hz), 7.78 (1H, dd, J
= 7.7, 1.1Hz), 8.67 (1H, s) FAB-MS; 524,526 (MH ⁺ )

Example 5 2- [N- (2'-methoxycarba
Rubonylbiphenyl-4-yl) methyl] cyclopropa
Carboxamide-5-bromo-4-methyl-3-nit
Synthesis of lopyridine To a solution of 3.14 g (28 mmol) of potassium t-butoxide in tetrahydrofuran (80 ml) was added 2-cyclopropanecarboxamide-5-bromo-4-methyl-3-nitropyridine 7.0.
g (23 mmol) was added and the mixture was stirred at room temperature for 1 hour. Next, this solution was heated, and under reflux, a solution of methyl 2- (4′-bromomethylphenyl) benzoate 8.5 g (28 mmol) in tetrahydrofuran (50 ml) was added dropwise, and stirring was continued for 1.5 hours after completion of the addition. The reaction mixture was returned to room temperature and ethyl acetate (200 ml) and saturated aqueous ammonium chloride solution (100 ml) were added for extraction. The aqueous layer was further extracted twice with ethyl acetate (100 ml), and the organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 13.3 g of an oily substance. The crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to give the title compound.
9.2 g was obtained. (Yield 75%)

Example 6 2- [N- (2'-methoxycarba
Rubonylbiphenyl-4-yl) methyl] cyclopropa
Carboxamide-5-bromo-4-methyl-3-nit
Synthesis of lopyridine In a solution of 2.47 g (22 mmol) of potassium t-butoxide in tetrahydrofuran (100 ml), 2-cyclopropanecarboxamide-5-bromo-4-methyl-3-nitropyridine 6.0
g (20 mmol) was added, and the mixture was stirred at room temperature for 1 hr. A solution of methyl 2- (4'-methanesulfonyloxymethylphenyl) benzoate 7.0 g (22 mmol) in tetrahydrofuran (60 ml) was added dropwise under heating and reflux, and the reaction was continued for 3 hours. The reaction mixture was cooled, added to saturated aqueous ammonium chloride solution, and extracted with chloroform. After washing the organic layer with water and drying,
It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to give the title compound (8.4 g). (80% yield)

Example 7 2- [N- (2'-methoxycarba
Rubonylbiphenyl-4-yl) methyl] cyclopropa
Carboxamide-5-bromo-4-methyl-3-nit
Synthesis of lopyridine In a solution of 3.14 g (28 mmol) of potassium t-butoxide in tetrahydrofuran (100 ml), 2-cyclopropanecarboxamide-5-bromo-4-methyl-3-nitropyridine 7.5
g (25 mmol) was added, and the mixture was stirred at room temperature for 45 minutes. A solution of methyl 2- (4'-p-toluenesulfonyloxymethylphenyl) benzoate 11.1 g (28 mmol) in tetrahydrofuran (50 ml) was added dropwise under heating and reflux, and the reaction was continued for 4 hours. The reaction mixture was cooled, added to saturated aqueous ammonium chloride solution, and extracted with chloroform. The organic layer was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to give the title compound (11.3 g). (Yield 86%)

Example 8 2- [N-cyclopropanal
Bonyl-N- {2 '-(4 ".4" -dimethyloxazo
Phosphorus-2 "-yl) biphenyl-4-yl} methyl] a
Of mino-5-bromo-4-methyl-3-nitropyridine
Synthesis

[0192]

[Chemical 55]

0.80 g (7.1 mmol) of potassium t-butoxide
To a tetrahydrofuran (15 ml) solution of was added 2.80 g (6.0 mmol) of 2-cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine, and after stirring at room temperature for 1 hour, 0.45 g (3.0 mmol of sodium iodide). ), N, N-dimethylformamide (10 ml) was added. Next, while heating under reflux, a tetrahydrofuran (20 ml) solution of 2,4-dimethyl-2- (4'-chloromethylbiphenyl-2-yl) oxazoline (2.50 g, 8.3 mmol) was added dropwise thereto, and stirring was continued for 13 hours. Continued. The reaction solution was cooled, added to saturated aqueous ammonium chloride solution, and extracted with chloroform. It was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to give the title compound (2.73 g). (Yield 81%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 0.74 ~
0.79 (2H, m), 1.07 to 1.12 (2H, m), 1.23 (6H, s), 1.55 to 1.65
(1H, m), 2.43 (3H, s), 3.77 (2H, s), 4.50-5.40 (2H, br), 7.2
5 to 7.40 (6H, m), 7.46 (1H, td, J = 8.0, 1.0Hz), 7.72 (1H, d, J
= 8.0Hz), 8.66 (1H, s) FAB-MS; 563,565 (MH ⁺ )

Example 9 2- [N-cyclopropanal
Bonyl-N- {2 '-(4 ".4" -dimethyloxazo
Phosphorus-2 "-yl) biphenyl-4-yl} methyl] a
Of mino-5-bromo-4-methyl-3-nitropyridine
To a solution of synthetic potassium / t-butoxide 0.74 g (6.6 mmol) in tetrahydrofuran (10 ml) was added 2-cyclopropanecarboxamide-5-bromo-4-methyl-3-nitropyridine.
1.52 g (5.1 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Next, under heating under reflux, 4,4-dimethyl-2- (4'-methanesulfonyloxymethylbiphenyl-2-yl) oxazoline 2.4 g (6.7 mmol) of dimethyl sulfoxide (10 ml) was added.
The solution was added dropwise and stirring was continued for 3 hours. The reaction mixture was cooled, added to saturated aqueous ammonium chloride solution, and extracted with chloroform. It was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to give 1.26 g of the title compound. (Yield 44%)

Example 10 2- [N-Cyclopropane Carbohydrate]
Rubonyl-N- {2 '-(4 ".4" -dimethyloxa
Zolin-2 "-yl) biphenyl-4-yl} methyl]
Amino-5-bromo-4-methyl-3-nitropyridine
In a solution of 0.67 g (6.0 mmol) of potassium t-butoxide in tetrahydrofuran (10 ml) was added 2-cyclopropanecarboxamide-5-bromo-4-methyl-3-nitropyridine.
1.50 g (5.0 mmol) was added, and the mixture was stirred at room temperature for 45 minutes. Next, under heating under reflux, 4,4-dimethyl-2- (4'-p-toluenesulfonyloxymethylbiphenyl-2-yl) was added thereto.
2.60 g (6.0 mmol) of oxazoline in tetrahydrofuran (20
(ml) solution was added dropwise and stirring was continued for 4 hours. The reaction solution was cooled, poured into a saturated aqueous solution of ammonium chloride, and extracted with chloroform. Chloroform (100 ml) was added to the aqueous layer.
It was extracted twice with. It was washed with water, dried, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: n-
(Hexane system) to obtain 1.40 g of the title compound. (Yield 50%)

Example 11 2- [N-Cyclopropane Carbohydrate]
Rubonyl-N- {2 '-(4 ".4" -dimethyloxa
Zolin-2 "-yl) biphenyl-4-yl} methyl]
Amino-5-bromo-4-methyl-3-nitropyridine
Synthesis of 2-cyclopropanecarboxamide-5-bromo-4-
Methyl-3-nitropyridine 1.5 g (5.0 mmol), 4,4-
Dimethyl-2- (4'-hydroxymethylbiphenyl-
1.4 g (5.0 mmol) of 2-yl) oxazoline and 0.89 g (5.0 mmol) of diethyl azodicarboxylate were dissolved in tetrahydrofuran (30 ml). After cooling to −70 ° C. and stirring for 2 hours, a solution of triphenylphosphine 1.3 g (5.0 mmol) in tetrahydrofuran (20 ml) was added dropwise. The mixture was stirred at −70 ° C. for 2 hours, then at room temperature for 12 hours, and at 50 ° C. for 5 hours. The solvent was evaporated under reduced pressure, ether (10 ml) was added to the residue, and the precipitated crystals were filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to obtain 2.0 g of the title compound. (Yield 7
1%)

Example 12 2- [N- (2'-methoxy
Carbonylbiphenyl-4-yl) methyl] cyclopro
Pancarboxamide-4-methyl-3-nitropyridine
Synthesis of

[0199]

[Chemical 56]

To a solution of 1.23 g (11 mmol) of potassium t-butoxide in tetrahydrofuran (30 ml) was added 2-cyclopropanecarboxamido-4-methyl-3-nitropyridine 2.0.
g (9 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The solution is then heated and under reflux, 2- (4'-bromomethylphenyl).
Methyl benzoate 8.5 g (28 mmol) of tetrahydrofuran (20
(ml) solution was added dropwise and stirring was continued for 2 hours after the completion of the addition. The reaction mixture was returned to room temperature and chloroform (200 ml) and saturated aqueous ammonium chloride solution (200 ml) were added for extraction. The aqueous layer was further extracted twice with chloroform (50 ml), the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane:
Purification with ethyl acetate) gave 3.4 g of the title compound.
(Yield 84%)

¹ H-NMR (600 MHz, CDCl ₃ ); δ (ppm) 0.62 ~
0.75 (2H, br), 0.98-1.11 (2H, br), 1.51 (1H, br-s), 2.36 (3
H, s), 3.55 (3H, s), 5.10 (2H, br-s), 7.00 to 7.34 (5H, m), 7.2
8 (1H, d, J = 7.5Hz), 7.32 (1H, dd, J = 7.5,7.5Hz), 7.43 (1H, d
d, J = 7.5, 7.5Hz), 7.72 (1H, d, J = 7.5Hz), 8.42 (1H, br-s) FAB-MS; 446 (MH ⁺ )

Example 13 2- [N- (2'-methoxy
Carbonylbiphenyl-4-yl) methyl] cyclopro
Pancarboxamide-4-methyl-3-nitropyridine
Synthesis of 2- [N- (2'-methoxycarbonylbiphenyl-4
-Yl) methyl] cyclopropanecarboxamide-5-
Bromo-4-methyl-3-nitropyridine 5.0 g (9.53 mm
ol), 10% Pd-C (100 mg), triethylamine 2.9 g (28.6 mmo
Toluene (100 ml) was added to (l) and the mixture was heated under reflux with stirring. 0.7 g (15.2 mmol) of formic acid was added dropwise thereto, and stirring was continued for 5 hours.
The reaction solution was returned to room temperature, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure.
Chloroform (200 ml) and water (200 ml) were added to the residue for liquid separation, and the aqueous layer was further extracted once with chloroform (100 ml). The organic layers are combined and dried over anhydrous magnesium sulfate,
It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to give the title compound (3.6 g). (Yield 85%)

Example 14 2-Cyclopropyl-3-
(2'-methoxycarbonylbiphenyl-4-yl) me
Tyl-6-bromo-7-methyl-3H-imidazo [4,4
Synthesis of 5-b] pyridine

[0204]

[Chemical 57]

2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] cyclopropanecarboxamide-5-bromo-4-methyl-3-nitropyridine
Ethanol (25 ml) was added to 1.0 g (1.9 mmol), iron powder (1.0 g) and acetic acid (2.5 ml), and the mixture was stirred with heating at 80 ° C. for 1 hour. The reaction solution was returned to room temperature, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure.
Chloroform (50 ml) and water (25 ml) were added to the residue for liquid separation,
The aqueous layer was further extracted once with chloroform (50 ml). The organic layers were combined, washed with an aqueous sodium hydrogen carbonate solution (25 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane:
Purification with chloroform) gave 0.54 g of the title compound.
(Yield 59%)

¹ H-NMR (600 MHz, CDCl ₃ ); δ (ppm) 0.98-
1.01 (2H, m), 1.14 to 1.16 (2H, m), 1.86 to 1.91 (1H, m), 2.59
(3H, s), 3.54 (3H, s), 5.51 (2H, s), 7.14 (2H, d, J = 8.4Hz), 7.
17 (2H, d, J = 8.4Hz), 7.22 (1H, dd, J = 7.5, 1.1Hz), 7.32 (1H,
ddd, J = 7.5, 7.5, 1.1Hz), 7.44 (1H, ddd, J = 7.5, 7.5, 1.1
Hz), 7.74 (1H, dd, J = 7.5, 1.1Hz), 8.28 (1H, s) FAB-MS; 446,448 (MH ⁺ )

Example 15 3-Cyclopropanecarboxy
Samide-2- [N- (2'-methoxycarbonylbiphe
Nyl-4-yl) methyl] amino-5-bromo-4-me
Synthesis of tylpyridine

[0208]

[Chemical 58]

2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] cyclopropanecarboxamide-5-bromo-4-methyl-3-nitropyridine
1.0 g (1.9 mmol), activated carbon (200 mg), hydrazine monohydrate 400 mg (7.99 mmol), ferric chloride hexahydrate 2.16 g (7.9
Methanol (50 ml) was added to 9 mmol), and the mixture was heated under reflux for 16 hours with stirring. The reaction solution was returned to room temperature, insoluble matters were removed by filtration through Celite, and the filtrate was concentrated under reduced pressure.
(00 ml) and water (100 ml) were added for liquid separation, and the aqueous layer was further extracted twice with chloroform (100 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: chloroform system) to give the title compound (0.65 g). (yield
69%)

¹ H-NMR (600 MHz, CDCl ₃ ); δ (ppm) 0.78 ~
0.80 (4H, m), 1.83 to 1.88 (1H, m), 2.07 (3H, s), 3.58 (3H, s),
4.57 (2H, d, J = 6.1Hz), 6.73 (1H, t, J = 6.1Hz), 7.19 (2H, d, J =
8.3Hz), 7.31 (2H, d, J = 8.3Hz), 7.39 (1H, dd, J = 7.6, 1.2H
z), 7.45 (1H, ddd, J = 7.6, 7.6 1.2Hz), 7.58 (1H, ddd, J = 7.
6, 7.6 1.2Hz), 7.69 (1H, dd, J = 7.6, 1.2Hz), 7.98 (1H, s),
9.47 (1H, s) FAB-MS; 494,496 (MH ⁺ )

Example 16 2-Cyclopropyl-3-
(2'-methoxycarbonylbiphenyl-4-yl) me
Tyl-6-bromo-7-methyl-3H-imidazo [4,4
Synthesis of 5-b] pyridine 3-Cyclopropanecarboxamide-2- [N- (2 ′
-Methoxycarbonylbiphenyl-4-yl) methyl]
Amino-5-bromo-4-methylpyridine 600 mg (1.21 m
mol), p-toluenesulfonic acid monohydrate 100 mg, and molecular sieves 4A (500 mg) were added with toluene (20 ml), and the mixture was heated under reflux for 2 hours with stirring. The reaction solution was returned to room temperature and the insoluble matter was removed by filtration through Celite. Chloroform (20 ml) in the filtrate,
Aqueous sodium hydrogen carbonate solution (50 ml) was added for liquid separation, and the aqueous layer was further extracted twice with chloroform (20 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to obtain 400 mg of the title compound. (Yield 69%)

Example 17 2-Cyclopropyl-3-
(2'-methoxycarbonylbiphenyl-4-yl) me
Tyl-7-methyl-3H-imidazo [4,5-b] pyri
Gin synthesis

[0213]

[Chemical 59]

2- [N- (2'-methoxycarbonylbiphenyl-4-yl) methyl] cyclopropanecarboxamide-5-bromo-4-methyl-3-nitropyridine
1.0 g (1.9 mmol), 10% Pd-C (40 mg), triethylamine 2.
Toluene (20 ml) was added to 9 g (29 mmol), and the mixture was heated under reflux with stirring. 1.0 g (22 mmol) of formic acid was added dropwise to this solution, and stirring was continued for 7 hours. The reaction solution was returned to room temperature, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. Chloroform (50 ml) and water (20 ml) were added to the residue for liquid separation, and the aqueous layer was further extracted twice with chloroform (20 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: chloroform system) to give the title compound (0.65 g). (Yield 86%)

¹ H-NMR (90 MHz, CDCl ₃ ); δ (ppm) 0.82 ~
1.30 (4H, m), 1.80-2.10 (1H, m), 2.64 (3H, s), 3.60 (3H, s),
5.62 (2H, s), 6.98 (1H, d, J = 5.0Hz), 7.22 (4H, s), 7.10 ~ 7.5
6 (3H, m), 7.63 ~ 7.85 (1H, m), 8.16 (1H, d, J = 5.0Hz) FAB-MS; 398 (MH ⁺ )

Example 18 2-Cyclopropyl-3-
(2'-methoxycarbonylbiphenyl-4-yl) me
Tyl-7-methyl-3H-imidazo [4,5-b] pyri
Synthesis of gin 2- [N- (2'-methoxycarbonylbiphenyl-4
-Yl) methyl] cyclopropanecarboxamide-5-
Bromo-4-methyl-3-nitropyridine 1.0 g (1.9 mmo
l), 10% Pd-C (100 mg), triethylamine 0.4 g (3.9 mmo
l) and acetic acid (5 ml) were added with ethanol (50 ml) and hydrogenation was carried out at normal pressure for 22 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. Chloroform (100 ml) and aqueous sodium hydrogen carbonate solution (100 ml) were added to the residue to separate the layers, and the aqueous layer was further extracted twice with chloroform (100 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to give the title compound (0.61 g). (Yield 80
%)

Example 19 2-Cyclopropyl-3-
(2'-methoxycarbonylbiphenyl-4-yl) me
Tyl-7-methyl-3H-imidazo [4,5-b] pyri
Synthesis of gin 2- [N- (2'-methoxycarbonylbiphenyl-4
-Yl) methyl] cyclopropanecarboxamide-5-
Bromo-4-methyl-3-nitropyridine 1.0 g (1.9 mmo
l), sodium borohydride 1.5 g (39 mmol), cupric chloride dihydrate 2.2 g (12.9 mmol), and i-propanol (100 ml)
Was added and the mixture was stirred with heating at 60 ° C. for 6 hours. The reaction solution was returned to room temperature, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. Chloroform (200 ml) and water (100 ml) were added to the residue for liquid separation, and the aqueous layer was further extracted twice with chloroform (50 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (n-hexane: chloroform system) to give 0.43 g of the title compound. (Yield 57%)

Example 20 2-Cyclopropyl-3-
(2'-methoxycarbonylbiphenyl-4-yl) me
Tyl-7-methyl-3H-imidazo [4,5-b] pyri
Synthesis of gin 2- [N- (2'-methoxycarbonylbiphenyl-4
-Yl) methyl] cyclopropanecarboxamide-5-
Bromo-4-methyl-3-nitropyridine 1.0 g (1.9 mmo
Tetrahydrofuran (100 ml) was added to l) and 10% Pd-C (400 mg), and the mixture was stirred. A 30% aqueous solution of sodium hypophosphite (20 ml) was added dropwise to this solution at room temperature over 1 hour, and the solution was further added at 60 ° C.
Stir for hours. The reaction solution was returned to room temperature, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. Chloroform (50 ml), water (20 ml) in the residue
Was added to separate the layers, and the aqueous layer was further extracted twice with chloroform (20 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: chloroform system) to give the title compound 0.35 g. (Yield 46%)

Example 21 2-Cyclopropyl-3-
(2'-methoxycarbonylbiphenyl-4-yl) me
Tyl-7-methyl-3H-imidazo [4,5-b] pyri
Synthesis of gin 2- [N- (2'-methoxycarbonylbiphenyl-4
-Yl) methyl] cyclopropanecarboxamide-5-
Bromo-4-methyl-3-nitropyridine 1.0 g (1.9 mmo
l), 10% Pd-C (50 mg), iron powder 2.0 g (35.8 mmol), acetic acid 10 ml
Ethanol (100 ml) was added to (175 mmol), and the mixture was heated under reflux for 11 hours. The reaction solution was returned to room temperature, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. Chloroform (200 ml) and water (100 ml) were added to the residue for liquid separation, and the aqueous layer was further extracted twice with chloroform (50 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: chloroform system) to give 0.46 g of the title compound. (Yield 61%)

Example 22 2-Cyclopropyl-3-
[2 '-(4 ", 4" -dimethyloxazoline-2 "-
Il) biphenyl-4-yl] methyl-7-methyl-3
Synthesis of H-imidazo [4,5-b] pyridine

[0221]

[Chemical 60]

2- [N-cyclopropanecarbonyl-N
-{2 '-(4 ", 4" -dimethyloxazoline-2 "
-Yl) biphenyl-4-yl} methyl] amino-5-
Bromo-4-methyl-3-nitropyridine 1.71 g (3.0 mm
ol) in toluene (100 ml), and 10% Pd-carbon catalyst (100 m
g), triethylamine 5.8 g (57.3 mmol), formic acid 1.40 g (3
0.4 mmol) was added and the mixture was heated under reflux for 10 hours. The reaction solution was cooled, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. Chloroform and water were added to the residue for extraction. It was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to give the title compound (1.02 g). (Yield 77%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.02-
1.12 (4H, m), 1.24 (6H, s), 1.93 to 2.01 (1H, m), 2.66 (3H, s),
3.47 (2H, s), 5.62 (2H, s), 7.03 (1H, d, J = 7.2Hz), 7.23 (2H, s
d, J = 8.0Hz), 7.30 to 7.35 (1H, m), 7.32 (2H, d, J = 8.0Hz), 7.3
6 (1H, td, J = 8.0, 1.0Hz), 7.47 (1H, td, J = 8.0, 1.0Hz), 7.7
3 (1H, d, J = 8.0Hz), 8.22 (1H, d, J = 7.2Hz) FAB-MS; 437 (MH ⁺ )

Example 23 2-Cyclopropyl-3-
(2'-methoxycarbonylbiphenyl-4-yl) me
Tyl-7-methyl-3H-imidazo [4,5-b] pyri
Synthesis of gin 2- [N- (2'-methoxycarbonylbiphenyl-4
-Yl) methyl] cyclopropanecarboxamide-4-
Methyl-3-nitropyridine 2.06 g (4.6 mmol), iron powder 2.
56 g (46.0 mmol), acetic acid 5 ml (87 mmol) in ethanol (100 ml)
Was added and the mixture was stirred with heating at 80 ° C. for 4 hours. The reaction solution was returned to room temperature, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. Chloroform (200 ml) and water (100 ml) were added to the residue for liquid separation, and the aqueous layer was further extracted twice with chloroform (50 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (n-hexane: chloroform system) to give the title compound (1.27 g). (Yield 69%)

Example 24 2-Cyclopropyl-3-
(2'-methoxycarbonylbiphenyl-4-yl) me
Tyl-7-methyl-3H-imidazo [4,5-b] pyri
Synthesis of gin 2-Cyclopropyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-6-bromo-7-methyl-3H-imidazo [4,5-b] pyridine 3.0 g (6.3m
mol), 10% Pd-C (100 mg), triethylamine 9.6 g (95 mmo
l) and toluene (30 ml) are mixed, and with stirring, formic acid 2.9 g (63 mmo
l) was added dropwise, and the mixture was heated under reflux for 10 hours. The reaction solution was returned to room temperature, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. Chloroform (100 ml) and water (100 ml) were added to the residue for liquid separation, and the aqueous layer was further extracted twice with chloroform (50 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to give the title compound (2.3 g). (Yield 92%)

Example 25 2-Cyclopropyl-3-
(2'-methoxycarbonylbiphenyl-4-yl) me
Tyl-7-methyl-3H-imidazo [4,5-b] pyri
Synthesis of gin 3-Cyclopropanecarboxamide-2- [N- (2 '
-Methoxycarbonylbiphenyl-4-yl) methyl]
Amino-5-bromo-4-methylpyridine 2.0 g (4.0 mmo
l), 10% Pd-C (100 mg), triethylamine 6.1 g (60 mmol)
And toluene (50 ml) were mixed and heated to reflux with stirring. 2.0 g (43 mmol) of formic acid was added dropwise thereto, and the mixture was heated under reflux for 7 hours. The reaction solution was returned to room temperature, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. Chloroform (100 ml) and water (100 ml) were added to the residue for liquid separation, and the aqueous layer was further extracted twice with chloroform (50 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: chloroform system) to give 1.45 g of the title compound. (Yield 90%)

Finally, it is an angiotensin II receptor antagonist useful as an antihypertensive agent, a therapeutic agent for vascular lesions, etc. 2
-Alkyl-3- (2'-carboxybiphenyl-4-
2-alkyl-methyl-3H-imidazo [4,5-b] pyridine derivative produced by using the active biphenyl derivative (IV) of the present invention as a synthetic intermediate.
Reference examples for producing the target compound from the 3- (biphenyl-4-yl) methyl-3H-imidazo [4,5-b] pyridine derivative (II) will be given.

[0228]

[Reference Example] Reference Example 1 2-cyclopropyl-3- (2 '
-Carboxybiphenyl-4-yl) methyl-7-methyl
Synthesis of Le-3H-imidazo [4,5-b] pyridine

[0229]

[Chemical formula 61]

2-Cyclopropyl-3- (2'-methoxycarbonylbiphenyl-4-yl) methyl-7-methyl-3H-imidazo [4,5-b] pyridine 1.32 g (3.3
Ethanol (40 ml) and 10% -sodium hydroxide aqueous solution (20 ml) were added to (mmol) and heated to reflux for 2 hours. After cooling the reaction mixture, the mixture was concentrated to about half the volume, neutralized with 2N-hydrochloric acid and acetic acid, and the precipitated crystals were collected by filtration. This was recrystallized from ethanol water to obtain 1.03 g of the title compound. (Yield 81%)

¹ H-NMR (600 MHz, DMSO-d ₆ ); δ (ppm) 1.06
(4H, m), 2.27 (1H, tt, J = 8.0, 5.0Hz), 2.50 (3H, s), 5.63 (2
H, s), 7.04 (1H, d, J = 5.0Hz), 7.27 (4H, m), 7.33 (1H, dd, J = 8.
0, 1.0Hz), 7.43 (1H, ddd, J = 8.0, 8.0, 1.0Hz), 7.54 (1H, d
dd, J = 8.0, 8.0, 2.0Hz), 7.70 (1H, dd, J = 8.0, 2.0Hz), 8.1
3 (1H, d, J = 5.0Hz), 12.70 (1H, br-s)

Reference Example 2 2-Cyclopropyl-3-
(2'-Carboxybiphenyl-4-yl) methyl-7
-Methyl-3H-imidazo [4,5-b] pyridine
Forming 2-cyclopropyl-3- [2 '- (4 ", 4" - dimethyl oxazoline -2 "- yl) biphenyl-4-yl] methyl-7-methyl -3H- imidazo [4,5-
b] 2.7 g (6.2 mmol) of pyridine was dissolved in ethanol (50 ml), 4N-hydrochloric acid (25 ml) was added, and the mixture was heated under reflux for 9 hr. The reaction mixture was cooled, added to saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. It was washed with water, dried, and concentrated under reduced pressure. The residue was dissolved in ethanol (25 ml), 2N-sodium hydroxide aqueous solution (25 ml) was added, and the mixture was heated under reflux for 6 hr. The reaction mixture was concentrated to dryness, water was added to dissolve the residue, and the mixture was neutralized with 2N-hydrochloric acid and acetic acid, and the precipitated crystals were collected by filtration. This was recrystallized from ethanol water to obtain 1.92 g of the title compound.
(Yield 81%)

Reference Example 3 2-Cyclopropyl-3-
(2'-Carboxybiphenyl-4-yl) methyl-7
-Methyl-3H-imidazo [4,5-b] pyridine
Forming 2-cyclopropyl-3- {2 '- (4 ", 4" - dimethyl oxazoline -2 "- yl) biphenyl-4-yl] methyl-7-methyl -3H- imidazo [4,5-
b] 5.0 g (11.5 mmol) of pyridine and water (8.7 ml) and sulfuric acid
5.3 g was added, and the mixture was heated under reflux for 36 hours. The pH was adjusted to 6 with a 10% aqueous sodium hydroxide solution and acetic acid, and the precipitated crystals were collected by filtration. This was recrystallized from ethanol water to give the title compound
Obtained 3.74 g. (Yield 85%)

Claims (15)

[Claims] 1. A 2- [N- (biphenyl-4-yl) methyl] alkylamido-3-nitropyridine derivative (I) represented by the following general formula: [In the formula, R ¹ means a hydrogen atom or a halogen atom, and the halogen atom means a bromine atom or a chlorine atom. R ² represents a hydrogen atom or a methyl group, and R ³ represents a cycloalkyl group, a lower alkyl group or a lower alkoxy group. R ⁴ is a group represented by the following general formula: (In the formula, R ⁵ represents a lower alkyl group, a cycloalkyl group, an alkoxyalkyl group, a thioalkoxyalkyl group, a cycloether group, an aryl group, an aralkyl group, an alkenyl group, an alkynyl group or a trialkylsilyl group.) Or the following. A group represented by the general formula: Means ] 2-Alkyl-3- (biphenyl-4-yl) methyl-3H- represented by the following general formula, characterized in that it is cyclized or cyclized / dehalogenated under reducing conditions.
Process for producing imidazo [4,5-b] pyridine derivative (II). [Chemical 4] [Wherein R ² , R ³ and R ⁴ have the same meanings as described above. ] 2. A 2-alkylamido-3-nitropyridine derivative (III) represented by the following general formula: [Wherein R ¹ , R ² and R ³ have the same meanings as described above. ]
Active biphenyl derivative (IV) represented by the following general formula: [Wherein Y represents a hydroxyl group, a halogen atom, a lower alkylsulfonyloxy group or an arylsulfonyloxy group, and R ⁴ has the same meaning as described above. ] -N-alkylation is carried out to give a 2- [N- (biphenyl-4-yl) methyl] alkylamido-3-nitropyridine derivative (I), which is then cyclized or cyclized / deprotected under reducing conditions. 2-alkyl-3- (biphenyl-4-yl) methyl-3H-imidazo [4,5] characterized by halogenation
-B] A method for producing a pyridine derivative (II). 3. 2-amino-3-represented by the following general formula:
The nitropyridine derivative (V) was converted to [In the formula, R ¹ and R ² have the same meanings as described above. ] A compound represented by the general formula R ³ COZ or (R ³ CO) ₂ O and [in the formula, Z means a leaving group in the organic synthesis reaction, and R ³ has the same meaning as described above. ] 2-Alkylamido-3-nitropyridine derivative (III) is reacted to react with active biphenyl derivative (IV) for N-alkylation to give 2- [N- (biphenyl-4-yl) methyl] 2-alkyl-3- (biphenyl-4-yl) methyl-3H-, characterized in that it is an alkylamido-3-nitropyridine derivative (I), which is then cyclized or cyclized / dehalogenated under reducing conditions. Process for producing imidazo [4,5-b] pyridine derivative (II). 4. A 2- [N- (biphenyl-4-yl) methyl] amino-3-alkylamidopyridine derivative (VI) represented by the following general formula: embedded image [Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above. ] 2-Alkyl-3- (biphenyl-4) characterized by cyclization or cyclization / dehalogenation under reducing conditions
-Yl) Methyl-3H-imidazo [4,5-b] pyridine derivative (II). 5. A 2- [N- (biphenyl-4-yl) methyl] alkylamido-3-nitropyridine derivative (I).
Is reduced and isomerized with activated carbon, hydrazine and ferric chloride to give 2- [N- (biphenyl-4-yl) methyl] amino-3-alkylamidopyridine derivative (VI), which is then cyclized under reducing conditions. A method for producing a 2-alkyl-3- (biphenyl-4-yl) methyl-3H-imidazo [4,5-b] pyridine derivative (II), which comprises cyclizing and dehalogenating. 6. A 2-alkyl-3 represented by the following general formula:
-(Biphenyl-4-yl) methyl-6-halogen-3
H-imidazo [4,5-b] pyridine derivative (VII) was converted to [In the formula, X represents a halogen atom, and R ² , R ³ and R ⁴ have the same meanings as described above. Further, the halogen atom means a bromine atom or a chlorine atom. ] 2-Alkyl-3- (biphenyl-4-) characterized by reduction / dehalogenation
Il) Methyl-3H-imidazo [4,5-b] pyridine derivative (II). 7. A 2-substituted 5-position is substituted with a halogen atom.
[N- (biphenyl-4-yl) methyl] alkylamido-3-nitropyridine derivative (I) is reduced / cyclized with iron / acetic acid or iron / hydrochloric acid to form 2-alkyl-3- (biphenyl-4-yl). Methyl-6-halogen-3H-imidazo [4,5-b] pyridine derivative (VII), followed by reduction / dehalogenation, 2-alkyl-3- (biphenyl-4-yl) methyl- Process for producing 3H-imidazo [4,5-b] pyridine derivative (II). 8. A 2- [N- (biphenyl-4-yl) methyl] amino-3-alkylamidopyridine derivative (VI).
2-alkyl-3- (biphenyl-4-yl) methyl-3H-imidazo which is cyclized under acidic conditions and further undergoes a reduction / dehalogenation reaction when R ¹ is a halogen atom. [4,5-b] Pyridine derivative (II)
Manufacturing method. 9. A 2- [N- (biphenyl-4-yl) methyl] alkylamido-3-nitropyridine derivative (I).
Is reduced and isomerized with activated carbon, hydrazine and ferric chloride to give 2- [N- (biphenyl-4-yl) methyl] amino-3-alkylamidopyridine derivative (VI), which is then cyclized under acidic conditions. 2-alkyl-3- (biphenyl-4-yl) methyl-3H-imidazo [4,5-b] pyridine characterized in that when R ¹ is a halogen atom, further reduction / dehalogenation reaction is carried out. Derivative (II)
Manufacturing method. 10. A 2-substituted 5-position is substituted with a halogen atom.
[N- (biphenyl-4-yl) methyl] alkylamido-3-nitropyridine derivative (I) is selectively reduced and dehalogenated to give 2- [N- (biphenyl-4-) represented by the following general formula. Iyl) methyl] alkylamido-3-nitropyridine derivative (VIII), and [Wherein R ² , R ³ and R ⁴ have the same meanings as described above. ]
Then, the method for producing a 2-alkyl-3- (biphenyl-4-yl) methyl-3H-imidazo [4,5-b] pyridine derivative (II), which comprises cyclizing under a reducing condition. 11. A 2-substituted 5-position is substituted with a halogen atom.
Alkylamido-3-nitropyridine derivative (III) is selectively reduced and dehalogenated to be represented by the following general formula 2
-Alkylamido-3-nitropyridine derivative (IX) was obtained, and [In the formula, R ² and R ³ have the same meanings as described above. ] Then, it is reacted with an active biphenyl derivative (IV) to give a 2- [N- (biphenyl-4-yl) methyl] alkylamido-3-nitropyridine derivative (VIII), which is then cyclized under reducing conditions. 2-alkyl-3- (biphenyl-4-yl) methyl-3H-imidazo [4,5-b]
Process for producing pyridine derivative (II). 12. A catalyst for reducing reaction and / or a reducing agent is a palladium-carbon catalyst and an amine / organic acid, a palladium-carbon catalyst and hydrogen, sodium borohydride / cupric chloride, a palladium-carbon catalyst and hypochlorous acid. Sodium phosphate,
The 2-alkyl-3- (biphenyl-4-yl) methyl-3H-imidazo [4] according to any one of claims 1 to 11, which is one selected from the combination of a palladium-carbon catalyst and iron / acetic acid. , 5-b] Pyridine derivative (II) production method. 13. A 2- [N- (biphenyl-4-yl) methyl] alkylamido-3-nitropyridine derivative (I) using triethylamine and formic acid or triethylamine and acetic acid as reducing agents in the presence of a palladium-carbon catalyst. 2-alkyl-3- characterized by reducing and cyclizing
Process for producing (biphenyl-4-yl) methyl-3H-imidazo [4,5-b] pyridine derivative (II). 14. A 2-alkylamido-3-nitropyridine derivative (X) represented by the following general formula: [Wherein R ¹ , R ² and R ³ have the same meanings as described above. R ⁶
Is a hydrogen atom or a group represented by the following general formula: (In the formula, R ⁷ is a group represented by the following general formula: {In the formula, R ⁸ represents a lower alkyl group, a cycloalkyl group, an alkoxyalkyl group, a thioalkoxyalkyl group, a cycloether group, an aryl group, an aralkyl group, an alkenyl group, an alkynyl group or a trialkylsilyl group. } Or a group represented by the following general formula: Means ) Means. ] 15. A 2- [N- (biphenyl-4-yl) methyl] amino-3-alkylamidopyridine derivative (VI) represented by the following general formula: [Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above. ]