JPH0761951A - Biphenylcarboxylic acid ester derivative - Google Patents

Abstract

PURPOSE:To obtain a new biphenylcarboxylic acid ester derivative useful as an antihypertensive agent, therapeutic agent for vascular lesion, etc., having angiotensin II receptor antagonism, by sulfonylating a hydroxymethylbiphenylcarboxylic acid ester derivative. CONSTITUTION:A hydroxymethylbiphenylcarboxylic acid ester derivative of formula I (R<2> is lower alkyl, aryl, aralkyl, cycloether, trialkylsilyl, triarylsilyl, vinyl, etc.) is sulfonylated with methanesulfonyl chloride in methylene chloride in the presence of triethylamine to give the objective biphenylcarboxylic acid ester derivative of formula II (R<1> is lower alkylsulfonyloxy or arylsulfonyloxy) as a substituent group precursor of angiotensin II receptor useful as an antihypertensive agent, therapeutic agent for vascular lesion, etc., in high yield, in high purity, safely and efficiently.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a sulfonyloxy-biphenylcarboxylic acid ester derivative (I) useful as a synthetic intermediate for pharmaceuticals, a method for producing the same, and an intermediate useful for producing the same. For further details, see Japanese Patent Laid-Open No. 3-95181
JP-A No. 3-236377, Japanese Patent Application No. 4-328986, etc., a substituent precursor of an angiotensin II receptor antagonist useful as an antihypertensive agent, therapeutic agent for vascular lesions, etc. The present invention relates to a sulfonyloxy-biphenylcarboxylic acid ester derivative (I), a method for producing the same, and an intermediate useful in the production.

[0002]

2. Description of the Related Art The biphenyl side of 2-alkyl-3- (2'-alkoxycarbonylbiphenyl-4-yl) methyl-3H-imidazo [4,5-b] pyridine derivatives, which are conventional angiotensin II receptor antagonists The chain has been produced by a method of N-alkylation using 4'-bromomethyl-2-biphenylcarboxylic acid ester, as described in JP-A-3-236377.

These 4'-bromomethyl-2-biphenylcarboxylic acid esters are described in Journal of Organic Chemistry (J. Org. Chem.), 43 (7), 1372-79, 1978.
4'-methyl-2-oxazolylbiphenyl was prepared by the method described in 1) and then hydrolyzed to 4'-methyl-2-
Biphenylcarboxylic acid, then esterified to 4'-
A methyl-2-biphenylcarboxylic acid ester is prepared, and then brominated by the method disclosed in JP-A-63-23868. This manufacturing process is shown below.

[0004]

[Chemical 11]

[0005]

[Problems to be Solved by the Invention] Conventionally used 4'-bromomethyl-2-biphenylcarboxylic acid ester has high activity and is easily reacted, but on the other hand, it is not stable due to its high activity and should be stored. I couldn't. 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 a 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, which makes purification difficult.

Further, in the production of 4'-bromomethyl-2-biphenylcarboxylic acid ester, in the method disclosed in JP-A-63-23868, N-bromosuccinimide is used for bromination. Has a drawback that it is not suitable for industrial production because it is expensive and the bromination is a radical reaction, so the reaction is rapid and difficult to control.

As described above, the conventionally used 4'-bromomethyl-2-biphenylcarboxylic acid ester is inferior in working efficiency as a synthetic intermediate and requires a lot of labor for separation and purification of N-alkylated products. However, it is not always satisfactory as an intermediate used in industrial production because it has drawbacks in economy and safety. Therefore, an industrially excellent active biphenyl intermediate capable of producing an imidazopyridine derivative, which is useful as an angiotensin II receptor antagonist, with high yield, high purity, and high economic efficiency has been desired.

[0008]

Therefore, the inventors of the present invention have conducted extensive studies toward an active biphenyl intermediate in which the above-mentioned drawbacks are improved. As a result, they have found that the sulfonyloxy-biphenylcarboxylic acid ester derivative (I) having the following general formula, which is a novel substance, is an excellent industrial intermediate having the above-mentioned necessary requirements, and completed the present invention.

[0009]

[Chemical 12]

In the formula, R ¹ is a lower alkylsulfonyloxy group or an arylsulfonyloxy group, and R ² is a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a trialkylsilyl group, a triarylsilyl group or a vinyl group. , Lower alkoxyalkyl group, aryloxyalkyl group, aralkyloxyalkyl group, thioalkoxyalkyl group or triphenylmethyl group.

The sulfonyloxy-biphenylcarboxylic acid ester derivative (I) according to the present invention can be produced by any of the following methods. (1) 4-Bromobenzyl alcohol is protected to a 4-bromobenzyl ether derivative (VI), and then oxazolylanisole is coupled by a Grineer reaction to an alkoxymethyl-biphenyloxazoline derivative (V), followed by deprotection. To a hydroxymethyl-biphenyloxazoline derivative (IV), then a deprotecting group to a hydroxymethyl-biphenylcarboxylic acid derivative (III), and then esterification to a hydroxymethyl-biphenylcarboxylic acid ester derivative (II), and Sulfonylation. (2) Methyl-biphenyloxazoline derivative (IX) is oxidized with an oxidizing agent to give a carboxy-biphenyloxazoline derivative (VII), which is then esterified with a lower alcohol to form an alkoxycarbonyl-biphenyloxazoline derivative.
(VIII) is reduced with a metal-hydrogen complex compound or immediately reduced with a metal-hydrogen complex compound to give a hydroxymethyl-biphenyloxazoline derivative (IV), which is then deprotected to form a hydroxymethyl-biphenylcarboxylic acid derivative (III).
And then esterified to the hydroxymethyl-biphenylcarboxylic acid ester derivative (II) and further sulfonylated.

The outline of the reaction route in the present invention is shown by the following chemical reaction formula.

[0013]

[Chemical 13]

In the formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above.

Therefore, an object of the present invention is 2-alkyl-3- (2'-alkoxycarbonylbiphenyl-4-yl) methyl-3H, which is an angiotensin II receptor antagonist useful as an antihypertensive agent and a therapeutic agent for vascular lesions. -Sulfonyloxy-biphenylcarboxylic acid ester derivative (I), which is a useful active intermediate for introducing a biphenyl side chain in the production of an imidazo [4,5-b] pyridine derivative, a method for producing the same, and further production thereof In providing a useful intermediate.

The sulfonyloxy-biphenylcarboxylic acid ester derivative (I) according to the present invention has the following general formula.

[0017]

[Chemical 14]

In the formula, R ¹ is a lower alkylsulfonyloxy group or an arylsulfonyloxy group, R ² is a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a trialkylsilyl group, a triarylsilyl group, a vinyl group, It means a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group.
Here, the lower alkylsulfonyloxy group for R ¹ is, for example, a group having an alkyl group having 1 to 6 carbon atoms in the molecule, such as a methanesulfonyloxy group or an ethanesulfonyloxy group, as an arylsulfonyloxy group. Examples thereof include a benzenesulfonyloxy group and a toluenesulfonyloxy group. The lower alkyl group for R ² is, for example, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t-butyl group, pentyl group, hexyl group. A group having 1 to 6 carbon atoms such as a group, an aryl group such as a phenyl group, a toluyl group and a xylyl group, an aralkyl group such as a benzyl group and a phenethyl group, and a cycloether group such as tetrahydropyranyl Groups, tetrahydrofuranyl groups, etc., trialkylsilyl groups such as trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, i-propyldimethylsilyl group, etc., triarylsilyl groups are triphenylsilyl group, phenyl A dimethylsilyl group or the like means a lower alkoxyalkyl group such as a methoxymethyl group, an ethoxymethyl group, a propoxymethyl group or a methoxy group. A cyethyl group, an ethoxyethyl group, a propoxyethyl group, a propoxypropyl group, etc., an aryloxyalkyl group such as a phenoxymethyl group, a phenoxyethyl group, a toluyloxymethyl group, and an aralkyloxyalkyl group such as a benzyloxymethyl group. Examples of the phenethyloxymethyl group and the thioalkoxyalkyl group include a methylthiomethyl group, a methylthioethyl group, an ethylthiomethyl group, a phenylthiomethyl group and a benzylthiomethyl group.

Specific examples of the sulfonyloxy-biphenylcarboxylic acid ester derivative (I) include the following compounds. The sulfonyloxy-biphenylcarboxylic acid ester derivative of the present invention is
(I) is not limited to these. (1) Methyl 2- (4'-methanesulfonyloxymethylphenyl) benzoate (2) Methyl 3- (4'-methanesulfonyloxymethylphenyl) benzoate (3) 4- (4'-Methanesulfonyloxymethylphenyl) ) Methyl benzoate (4) Ethyl 2- (4'-methanesulfonyloxymethylphenyl) benzoate (5) Ethyl 3- (4'-methanesulfonyloxymethylphenyl) benzoate (6) 4- (4'-methane Ethyl sulfonyloxymethylphenyl) benzoate (7) Methyl 2- (4'-ethanesulfonyloxymethylphenyl) benzoate (8) Methyl 3- (4'-ethanesulfonyloxymethylphenyl) benzoate (9) 4- ( Methyl 4'-ethanesulfonyloxymethylphenyl) benzoate (10) 2- (4'-ethanesulfonyloxymethylphenyl) ethyl benzoate (11) 3- Ethyl (4'-ethanesulfonyloxymethylphenyl) benzoate (12) 4- (4'-ethanesulfonyloxymethylphenyl) ethyl benzoate (13) 2- (4'-p-toluenesulfonyloxymethylphenyl) benzoic acid Methyl (14) 3- (4'-p-toluenesulfonyloxymethylphenyl) benzoate Methyl (15) 4- (4'-p-toluenesulfonyloxymethylphenyl) benzoate (16) 2- (4'- Ethyl p-toluenesulfonyloxymethylphenyl) benzoate (17) 3- (4'-p-toluenesulfonyloxymethylphenyl) ethyl benzoate (18) 4- (4'-p-toluenesulfonyloxymethylphenyl) benzoic acid Ethyl (19) 2- (4'-benzenesulfonyloxymethylphenyl) methyl benzoate (20) 3- (4'-Benzenesulfonyloxymethyl) Methyl (21) 4- (4'-benzenesulfonyloxymethylphenyl) benzoate (22) 2- (4'-benzenesulfonyloxymethylphenyl) benzoate Ethyl (23) 3- (4'- Benzenesulfonyloxymethylphenyl) ethyl benzoate (24) 4- (4'-benzenesulfonyloxymethylphenyl) ethyl benzoate

Next, the hydroxymethyl-biphenylcarboxylic acid ester derivative (II) according to the present invention has the following general formula.

[0021]

[Chemical 15]

In the formula, R ² has the same meaning as described above. Specific examples thereof include the following compounds, but the hydroxymethyl-biphenylcarboxylic acid ester derivative (II) according to the present invention is not limited thereto. (1) Methyl 2- (4'-hydroxymethylphenyl) benzoate (2) Methyl 3- (4'-hydroxymethylphenyl) benzoate (3) Methyl 4- (4'-hydroxymethylphenyl) benzoate (4 ) Ethyl 2- (4'-hydroxymethylphenyl) benzoate (5) Ethyl 3- (4'-hydroxymethylphenyl) benzoate (6) Ethyl 4- (4'-hydroxymethylphenyl) benzoate

Next, the hydroxymethyl-biphenylcarboxylic acid derivative (III) has the following chemical structural formula.

[0024]

[Chemical 16]

Specific examples of the hydroxymethyl-biphenylcarboxylic acid derivative (III) include the following compounds, but the hydroxymethyl-biphenylcarboxylic acid derivative (III) in the present invention is not limited thereto. (1) 2- (4'-hydroxymethylphenyl) benzoic acid (2) 3- (4'-hydroxymethylphenyl) benzoic acid (3) 4- (4'-hydroxymethylphenyl) benzoic acid

The hydroxymethyl-biphenyloxazoline derivative (IV) according to the present invention has the following chemical structural formula.

[0027]

[Chemical 17]

More specifically, the following compounds can be specifically mentioned, but the hydroxymethyl-biphenyloxazoline derivative (IV) according to the present invention is not limited thereto. (1) 4,4-Dimethyl-2- (4'-hydroxymethylbiphenyl-2-yl) oxazoline (2) 4,4-Dimethyl-2- (4'-hydroxymethylbiphenyl-3-yl) oxazoline (3 ) 4,4-Dimethyl-2- (4'-hydroxymethylbiphenyl-4-yl) oxazoline

Next, the alkoxymethyl-biphenyloxazoline derivative (V) has the following chemical structural formula.

[0030]

[Chemical 18]

In the formula, R ³ is a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a lower alkoxyalkoxyalkyl group, a thioalkoxyalkyl group, a cycloether group, a trialkylsilyl group, a triarylsilyl group, a lower alkyl. Group, vinyl group, aralkyl group or triphenylmethyl group.

More specifically, as the lower alkoxyalkyl group, for example, a methoxymethyl group, an ethoxymethyl group, a propoxymethyl group, a methoxyethyl group, an ethoxyethyl group, a propoxyethyl group, a propoxypropyl group or the like is used as an aryloxyalkyl group. Examples of groups include phenoxymethyl group, phenoxyethyl group, toluyloxymethyl group and the like, examples of aralkyloxyalkyl group such as benzyloxymethyl group and phenethyloxymethyl group, and examples of lower alkoxyalkoxyalkyl group such as methoxyethoxymethyl group and ethoxyethoxy. A methyl group or the like is used as a thioalkoxyalkyl group, for example, a methylthiomethyl group, a methylthioethyl group, an ethylthiomethyl group, a phenylthiomethyl group, a benzylthiomethyl group or the like is used as a cycloether. For example, a tetrahydropyranyl group, a tetrahydrofuranyl group or the like, a trialkylsilyl group such as a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, an i-propyldimethylsilyl group or the like, a triarylsilyl group such as triphenyl A silyl group, a phenyldimethylsilyl group, etc., a lower alkyl group such as a methyl group, an ethyl group, a propyl group, a t-butyl group, etc., and an aralkyl group such as a benzyl group, a phenethyl group, a methylbenzyl group, a trimethylbenzyl group, a nitro group. Examples thereof include a benzyl group and a phenacyl group.

Further, the following compounds can be mentioned as specific representative examples of the alkoxymethyl-biphenyloxazoline derivative (V), but the alkoxymethyl-biphenyloxazoline derivative (V) according to the present invention is not limited thereto. .

(1) 4,4-Dimethyl-2- (4'-methoxymethoxymethylbiphenyl-2-yl) oxazoline (2) 4,4-Dimethyl-2- (4'-methoxyethoxymethoxymethylbiphenyl-2) -Yl) oxazoline (3) 4,4-dimethyl-2- (4'-thiomethoxymethoxymethylbiphenyl-2-yl) oxazoline (4) 4,4-dimethyl-2- (4'-tetrahydropyranyloxymethyl Biphenyl-2-yl) oxazoline (5) 4,4-dimethyl-2- (4'-tetrahydrofuranyloxymethylbiphenyl-2-yl) oxazoline (6) 4,4-dimethyl-2- (4'-trimethylsilyloxy) Methylbiphenyl-2-yl) oxazoline (7) 4,4-dimethyl-2- (4'-t-butoxymethylbiphenyl-2-yl) oxazoline (8) 4, - dimethyl-2- (4'-benzyloxy-methylbiphenyl-2-yl) oxazoline

Further, the 4-bromobenzyl ether derivative (VI) according to the present invention has the following chemical structural formula.

[0036]

[Chemical 19]

In the formula, R ³ has the same meaning as described above. Four
Specific examples of the -bromobenzyl ether derivative (VI) include the following compounds, but the 4-bromobenzyl ether derivative (VI) in the present invention is not limited thereto. (1) 4-Bromobenzyl-methoxymethyl ether (2) 4-Bromobenzyl-methoxyethoxymethyl ether (3) 4-Bromobenzyl-thiomethoxymethyl ether (4) 4-Bromobenzyl-tetrahydropyranyl ether (5) 4 -Bromobenzyl-tetrahydrofuranyl ether (6) 4-Bromobenzyl-trimethylsilyl ether (7) 4-Bromobenzyl-t-butyl ether (8) 4-Bromobenzyl-benzyl ether

Further, the carboxy-biphenyloxazoline derivative (VII) according to the present invention has the following chemical structural formula.

[0039]

[Chemical 20]

More specifically, the following compounds may be mentioned, but the carboxy-biphenyloxazoline derivative (VII) in the present invention is not limited to these. (1) 4,4-Dimethyl-2- (4'-carboxylbiphenyl-2-yl) oxazoline (2) 4,4-Dimethyl-2- (4'-carboxylbiphenyl-3-yl) oxazoline (3) 4 , 4-Dimethyl-2- (4'-carboxylbiphenyl-4-yl) oxazoline

Further, the alkoxycarbonyl-biphenyloxazoline derivative (VIII) according to the present invention has the following chemical structural formula.

[0042]

[Chemical 21]

In the formula, R ⁴ is a lower alkyl group, an aryl group,
It means an aralkyl group, a cycloether group, a trialkylsilyl group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group. Here, the lower alkyl group specifically includes, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group and the like having 1 to 1 carbon atoms.
6, the aryl group is, for example, a phenyl group, a toluyl group, a xylyl group, etc., the aralkyl group is, for example, a benzyl group, a phenethyl group, etc., and the cycloether group is, for example, a tetrahydropyranyl group, a tetrahydrofuranyl group, etc. ,
The trialkylsilyl group is, for example, a trimethylsilyl group,
A triethylsilyl group, a t-butyldimethylsilyl group, an i-propyldimethylsilyl group or the like, a triarylsilyl group such as a triphenylsilyl group or a phenyldimethylsilyl group, and a lower alkoxyalkyl group such as a methoxymethyl group, Ethoxymethyl group, propoxymethyl group,
A methoxyethyl group, an ethoxyethyl group, a propoxyethyl group, a propoxypropyl group, etc., an aryloxyalkyl group such as a phenoxymethyl group, a phenoxyethyl group, a toluyloxymethyl group, etc., and an aralkyloxyalkyl group such as benzyloxymethyl group. Examples of the thioalkoxyalkyl group include a methylthiomethyl group, a methylthioethyl group, an ethylthiomethyl group, a phenylthiomethyl group, and a benzylthiomethyl group. Specific examples of the alkoxycarbonyl-biphenyloxazoline derivative (VIII) include the following compounds, but the alkoxycarbonyl-biphenyloxazoline derivative (VIII) in the present invention is not limited thereto. (1) 4,4-Dimethyl-2- (4'-methoxycarbonylbiphenyl-2-yl) oxazoline (2) 4,4-Dimethyl-2- (4'-ethoxycarbonylbiphenyl-2-yl) oxazoline (3 ) 4,4-Dimethyl-2- (4'-propoxycarbonylbiphenyl-2-yl) oxazoline (4) 4,4-Dimethyl-2- (4'-phenoxycarbonylbiphenyl-2-yl) oxazoline (5) 4 , 4-Dimethyl-2- (4'-benzyloxycarbonylbiphenyl-2-yl) oxazoline (6) 4,4-Dimethyl-2- (4'-tetrahydropyranyloxycarbonylbiphenyl-2-yl) oxazoline

Further, the methyl-biphenyloxazoline derivative (IX) according to the present invention has the following chemical structural formula.

[0045]

[Chemical formula 22]

The following compounds can be mentioned as specific representative examples, but the methyl-biphenyloxazoline derivative (IX) according to the present invention is not limited thereto. (1) 4,4-Dimethyl-2- (4'-methylbiphenyl-2-yl) oxazoline (2) 4,4-Dimethyl-2- (4'-methylbiphenyl-3-yl) oxazoline (3) 4 , 4-dimethyl-2- (4'-methylbiphenyl-4-yl) oxazoline

Next, each step of the production method according to the present invention will be described in detail below (the above chemical reaction formula [Chemical Formula 13]). Step 1 This step protects 4-bromobenzyl alcohol and
In this step, the bromobenzyl ether derivative (VI) is obtained. This step can be carried out according to a conventional method for introducing a protective group for a hydroxyl group in organic synthesis. Specific examples of the protecting group-introducing reagent that can be used in the present invention include chloromethyl methyl ether, 2-chloroethyl methyl ether, chloromethyl phenyl ether, chloromethyl benzyl ether, chloromethyl methoxyethyl ether, and chloromethyl methyl sulfide. , Dihydropyran, dihydrofuran, chlorotrimethylsilane, chlorotriethylsilane, chlorotriphenylsilane, methyl iodide, benzyl chloride, chlorotriphenylmethane and the like.

Step 2 This step is a step of coupling the 4-bromobenzyl ether derivative (VI) and oxazolylanisole by a Grineer reaction to give an alkoxymethyl-biphenyloxazoline derivative (V). This reaction is based on the Journal of Organic Chemistry (J.Org.Chem.), 4
3 (7), 1372-79, 1978. etc., and can be carried out according to the usual method of Grineer reaction.

Step 3 In this step, the protecting group of the alkoxymethyl-biphenyloxazoline derivative (V) is removed to produce the hydroxymethyl-biphenyloxazoline derivative (IV). This reaction can be carried out according to a general protecting group elimination method such as hydrolysis or catalytic reduction.

Step 4 Step 4 is a methyl-biphenyloxazoline derivative (IX)
To carboxy-biphenyloxazoline derivative
This is the step (VII). An oxidant is used in this reaction, and specific examples of the oxidant that can be used in the present invention include, for example, permanganate, chromium oxide, and dichromate, with permanganate being more preferred. . Also, this reaction is based on Organic Synthesis
Synthesis), Col. Vol. II, 135. etc., but in the present invention, methyl-biphenyloxazoline derivative (IX) is dissolved in a solvent, permanganate such as potassium permanganate. Add salt and heat.

The amount of permanganate used is not limited, but is usually a methyl-biphenyloxazoline derivative (IX).
1 to 100 equivalents, more preferably about 1 to 100 equivalents of
2 to 50 equivalents are used, more preferably about 3 to 20 equivalents.

The solvent used in this reaction is not limited as long as it is inert to the methyl-biphenyloxazoline derivative (IX) or the oxidizing agent, and specifically, for example, water, pyridine, formic acid, acetic acid, etc. Can be mentioned. The solvent may be used alone or as a mixture of two or more kinds. Although the amount of the solvent used is not limited, it is usually about 0.5 to 100 volume, more preferably about 0.5 to 50 volume, and still more preferably about 1 to 20 volume with respect to 1 weight of the methyl-biphenyloxazoline derivative (IX). To use.

This reaction is usually carried out by heating at 50 ° C. to solvent reflux temperature. The reaction time varies depending on the kind, amount, temperature and the like of the oxidizing agent, but it is usually completed in 1 to 48 hours.

Step 5 and Step 7 This step is a carboxy-biphenyloxazoline derivative
(VII) or an alkoxycarbonyl-biphenyloxazoline derivative (VIII) is reduced with a metal hydrogen complex compound to give a hydroxymethyl-biphenyloxazoline derivative (IV). Specific examples of the metal-hydrogen complex compound in the present invention include lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, diisobutylaluminum hydride, diborane and the like. The amount of the metal-hydrogen complex compound used is not limited, but is usually about 0.2 to 50 per 1 equivalent of the carboxy-biphenyloxazoline derivative (VII) or the alkoxycarbonyl-biphenyloxazoline derivative (VIII).
The equivalent is used, more preferably about 0.5 to 20 equivalents, and even more preferably about 1 to 10 equivalents.

In this reaction, it is preferable to use a solvent. The solvent that can be used is not limited as long as it is inert to the carboxy-biphenyloxazoline derivative (VII) or the alkoxycarbonyl-biphenyloxazoline derivative (VIII) or the metal hydrogen complex compound. Specific examples include, for example, tetrahydrofuran, 1,2-dimethoxyethane, ethyl ether, isopropyl ether, 2-
Methoxyethyl ether, dioxane, dioxolane,
Examples thereof include benzene, toluene, hexane and octane. The solvent may be a single solvent or a mixture of two or more kinds. Although the amount used is not limited, it is usually a carboxy-biphenyloxazoline derivative (VII).
Alternatively, the amount of the alkoxycarbonyl-biphenyloxazoline derivative (VIII) is about 0.5 to 100 volume, more preferably about 0.5 to 50 volume, still more preferably about 1 to 2 with respect to 1 weight thereof.
Use 0 volume.

This reaction can be carried out usually at -70 ° C to solvent reflux temperature, but it is usually carried out under ice cooling. The reaction time varies depending on the kind, amount, temperature and the like of the metal-hydrogen complex compound, but it is usually completed in about 5 minutes to 6 hours.

Step 6 This step is a step of esterifying the carboxy-biphenyloxazoline derivative (VII) obtained in Step 4 to give an alkoxycarbonyl-biphenyloxazoline derivative (VIII). This reaction can be carried out according to a general ester synthesis method.

Step 8 In this step, the hydroxymethyl-biphenyloxazoline derivative (IV) is deprotected to obtain the hydroxymethyl-biphenylcarboxylic acid derivative (III). This reaction is a conventional method of organic synthesis in which oxazoline is hydrolyzed to a carboxylic acid, that is, acid hydrolysis, base hydrolysis, Journal of Organic Chemistry (J.Org.
Chem.), 3 9 (3 ), 2778,1974. Can be carried out by the method, or a combination thereof or the like using sodium hydroxide and methyl iodide as described in, sulfuric acid hydrolysis in the present invention, hydrochloric acid hydrolysis And a combination of hydrolysis with sodium hydroxide, or a method using the above methyl iodide and sodium hydroxide is preferable.

Step 9 This step is a step of esterifying the hydroxymethyl-biphenylcarboxylic acid derivative (III) to give a hydroxymethyl-biphenylcarboxylic acid ester derivative (II). This reaction can be carried out according to a general ester synthesis method.

Step 10 This step is a step of producing a sulfonyloxy-biphenylcarboxylic acid ester derivative (I) by sulfonylating the hydroxymethyl-biphenylcarboxylic acid ester derivative (II).

In the present invention, methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride,
It is carried out according to a conventional method using a sulfonylating reagent such as p-toluenesulfonyl chloride. The amount of the sulfonylating reagent used is not limited, but is usually about 1 per 1 equivalent of the hydroxymethyl-biphenylcarboxylic acid ester derivative (II).
~ 50 equivalents, more preferably about 1.2-20 equivalents, and even more preferably about 1.5-10 equivalents are used.

The sulfonyloxy-biphenylcarboxylic acid ester derivative (I) according to the present invention has high stability and can be further purified by a conventional method such as silica gel column chromatography or vacuum distillation.

Next, the hydroxymethyl-biphenylcarboxylic acid derivative (X) represented by the following general formula is a novel compound, and is an intermediate in the production of the sulfonyloxy-biphenylcarboxylic acid ester derivative (I) of the present invention. Is useful as

[0064]

[Chemical formula 23]

In the formula, R ⁵ is a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a trialkylsilyl group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group or an aralkyloxy group. It means an alkyl group, a thioalkoxyalkyl group or a triphenylmethyl group.

More specifically, as the lower alkyl group, for example, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a t-butyl group, a pentyl group, A group having 1 to 6 carbon atoms such as a hexyl group, an aryl group such as a phenyl group, a toluyl group, and a xylyl group, an aralkyl group such as a benzyl group, a phenethyl group, and the like, a cycloether group such as a tetrahydropyranyl group, and the like. Tetrahydrofuranyl group, etc., as trialkylsilyl group such as trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, i-propyldimethylsilyl group, etc., as triarylsilyl group such as triphenylsilyl group, phenyldimethylsilyl group Etc. as lower alkoxyalkyl groups such as methoxymethyl group, ethoxymethyl group , A propoxymethyl group, a methoxyethyl group, an ethoxyethyl group, a propoxyethyl group, a propoxypropyl group and the like, an aryloxyalkyl group such as a phenoxymethyl group, a phenoxyethyl group, a toluyloxymethyl group and the like, an aralkyloxyalkyl group such as Examples of the thioalkoxyalkyl group include a benzyloxymethyl group and a phenethyloxymethyl group, and examples thereof include a methylthiomethyl group, a methylthioethyl group, an ethylthiomethyl group, a phenylthiomethyl group, and a benzylthiomethyl group.

The following compounds may be mentioned as more specific representative examples of the hydroxymethyl-biphenylcarboxylic acid derivative (X). The hydroxymethyl-biphenylcarboxylic acid derivative (X) of the present invention is Not limited to. (1) 2- (4'-hydroxymethylphenyl) benzoic acid (2) 3- (4'-hydroxymethylphenyl) benzoic acid (3) 4- (4'-hydroxymethylphenyl) benzoic acid (4) 2- Methyl (4'-hydroxymethylphenyl) benzoate (5) Ethyl 2- (4'-hydroxymethylphenyl) benzoate (6) Propyl 2- (4'-hydroxymethylphenyl) benzoate (7) 2- (4 '-Hydroxymethylphenyl) benzoic acid
Phenyl t-butyl (8) 2- (4'-hydroxymethylphenyl) benzoate (9) Benzyl 2- (4'-hydroxymethylphenyl) benzoate (10) 2- (4'-hydroxymethylphenyl) benzoic acid Tetrahydropyranyl (11) 2- (4'-hydroxymethylphenyl) benzoate Tetrahydrofuranyl (12) 2- (4'-hydroxymethylphenyl) benzoate Trimethylsilyl (13) 2- (4'-hydroxymethylphenyl) benzoate Acid methoxymethyl (14) 2- (4'-hydroxymethylphenyl) benzoic acid thiomethoxymethyl

Next, production examples for producing the starting materials necessary for carrying out the present invention will be listed prior to the examples.

[0069]

[Production Example] Production Example 1 4-Bromobenzyl-methoxymethyl ether
Synthesis

[0070]

[Chemical formula 24]

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

[0074]

[Chemical 25]

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 the title compound as an oil 12.
I got 0g. (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 (1
H, d, J = 13.0Hz), 4.64 (1H, s), 4.70 (1H, d, J = 13.0Hz), 7.18
(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

[0078]

[Chemical formula 26]

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
-Dimethyl-2- (2'-methoxyphenyl) oxazoline 10.0 g (48.7 mmol) in tetrahydrofuran (100 ml) was added dropwise to the solution, 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), 7.00-7.50 (7H, m), 7.70 (1H, dd, J = 7.5,
1.5Hz) FAB-MS; 266 (MH ⁺ )

Next, in order to specifically describe the present invention,
Examples will be given below, but it goes without saying that the present invention is not limited thereto.

【Example】

Example 1 4,4-dimethyl-2- (4 '
-Methoxymethoxymethylbiphenyl-2-yl) oxy
Sazoline synthesis

[0083]

[Chemical 27]

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), 7.7
3 (1H, dd, J = 8.0, 1.5Hz) FAB-MS; 326 (MH ⁺ )

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

[0087]

[Chemical 28]

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), 1.50-1.94 (6H, m), 3.52-3.59 (1H, m), 3.80 (2H, s), 3.
91-3.97 (1H, m), 4.55 (1H, d, J = 12.3Hz), 4.73 (1H, t, J = 3.7H
z), 4.84 (1H, d, J = 12.3Hz), 7.38 (4H, s), 7.34-7.40 (2H, 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 ⁺ )

Example 3 4,4-dimethyl-2- (4 '
-Hydroxymethylbiphenyl-2-yl) oxazoli
Synthesis

[0091]

[Chemical 29]

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), 7.35-7.42
(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 ⁺ )

Example 4 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%)

Example 5 4,4-Dimethyl-2- (4 '
-Carboxybiphenyl-2-yl) oxazoline
Success

[0096]

[Chemical 30]

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 permanganate was heated under reflux. 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), 7.43-7.48 (4H, m), 7.49 (1H, dt, J = 7.5, 1.5Hz), 7.58
(1H, dd, J = 7.5,1.0Hz), 7.96 (2H, dd, J = 8.6, 1.9Hz), 12.90
(1H, br) FAB-MS; 296 (MH ⁺ )

Example 6 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 give the title compound (4.2 g). (88% yield)

Example 7 4,4-Dimethyl-2- (4 '
-Methoxycarbonylbiphenyl-2-yl) oxazo
Phosphorus synthesis

[0101]

[Chemical 31]

4,4-Dimethyl-2- (4'-carboxybiphenyl-2-yl) oxazoline 10.0 g (33.8 mmo
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), 7.28-7.56 (5H, m), 7.75 (1
H, d, J = 8.5Hz), 8.03 (2H, d, J = 7.5Hz) FAB-MS; 310 (MH ⁺ )

Example 8 4,4-Dimethyl-2- (4 '
-Hydroxymethylbiphenyl-2-yl) oxazoli
Synthesis of 4,4-dimethyl-2- (4′-methoxycarbonylbiphenyl-2-yl) oxazoline 2.0 g (6.46 mmol) 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%)

Example 9 2- (4'-hydroxymethyl)
Synthesis of (phenyl) benzoic acid

[0106]

[Chemical 32]

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 ⁺ )

Example 10 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%)

Example 11 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%)

Example 12 2- (4'-hydroxymethyi)
Synthesis of methyl ruphenyl) benzoate 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 ⁺ )

Example 13 2- (4'-methanesulfoni
Synthesis of methyl luoxymethylphenyl) benzoate

[0114]

[Chemical 33]

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)

Example 14 2- (4'-p-toluene sulphate
Synthesis of methyl phenyloxymethylphenyl) benzoate

[0118]

[Chemical 34]

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 at room temperature 2
After reacting for an hour, the mixture was heated under reflux for an additional 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), 6.96-7.60 (3H, m), 7.77 (2H, d, J = 7.7Hz), 7.64-7.9
0 (1H, m)

Finally, it is an angiotensin II receptor antagonist useful as an antihypertensive agent, a therapeutic agent for vascular lesions, etc.
Alkyl-3- (2'-alkoxycarbonylbiphenyl-4-yl) methyl-3H-imidazo [4,5-b]
In producing a pyridine derivative, the sulfonyloxy-biphenylcarboxylic acid ester derivative (I) according to the present invention
In order to show the usefulness as a synthetic intermediate of, a reference example is given below.

[0122]

[Reference Example] Reference Example 1 2- [N- (2'-methoxycarbonylbiph
[4-phenyl) methyl] cyclopropanecarboxa
Of mido-5-bromo-4-methyl-3-nitropyridine
Synthesis

[0123]

[Chemical 35]

2.47 g (22.0 mmol) of potassium t-butoxide
To a tetrahydrofuran (100 ml) solution of was added 6.00 g (20.0 mmol) of 2-cyclopropanecarboxamide-5-bromo-4-methyl-3-nitropyridine, and the mixture was stirred at room temperature for 1 hour. Next, with heating under reflux, methyl 2- (4'-methanesulfonyloxymethylphenyl) benzoate 7.00 g
A solution of (22.0 mmol) in tetrahydrofuran (60 ml) was added dropwise,
The stirring was continued for 3 hours as it was. 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 (ethyl acetate: n-hexane system) to give 8.40 g of the title compound as an oil. (yield
80%)

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 ⁺ )

Reference Example 2 2- [N- (2'-methoxycarboxa]
Rubonylbiphenyl-4-yl) methyl] cyclopropa
Carboxamide-5-bromo-4-methyl-3-nit
Synthesis of Ropyridine In a solution of 3.14 g (28.0 mmol) of potassium t-butoxide in tetrahydrofuran (100 ml) was added 2-cyclopropanecarboxamide-5-bromo-4-methyl-3-nitropyridine.
7.50 g (25.0 mmol) was added, and the mixture was stirred at room temperature for 45 minutes. Next, under heating under reflux, 11.10 g (28.0 g) of methyl 2- (4'-p-toluenesulfonyloxymethylphenyl) benzoate was added.
A tetrahydrofuran (50 ml) solution of (mmol) 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. The aqueous layer was further extracted with chloroform. It was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane system) to give 11.30 g of the title compound as an oil. (Yield 86%)

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

[0128]

[Chemical 36]

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 ⁺ )

Reference Example 4 2-Cyclopropyl-3-
(2'-Carboxybiphenyl-4-yl) methyl-7
-Methyl-3H-imidazo [4,5-b] pyridine
Success

[0132]

[Chemical 37]

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 0 mmol) and the mixture was heated under 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)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07C 319/20 323/12 7419-4H C07F 7/18 A // C07D 263/10 263/14 ( 72) Inventor Yoji Yamagishi 2010-46 Kaminayoshi, Chiyoda-cho, Shinji-gun, Ibaraki 2010-46 (72) Inventor Tomio Tsurugi 1-1044-130, Toyosatodai, Choshi-shi, Chiba (72) Tomio Ichino Miyaka Kashima-cho, Kashima-gun, Ibaraki 2333-197

Claims (11)

[Claims] 1. A sulfonyloxy- having the following general formula:
Biphenylcarboxylic acid ester derivative (I). [Chemical 1] [Wherein R ¹ is a lower alkylsulfonyloxy group or an arylsulfonyloxy group, R ² is a lower alkyl group,
Aryl group, aralkyl group, cycloether group, trialkylsilyl group, triarylsilyl group, vinyl group, lower alkoxyalkyl group, aryloxyalkyl group,
It means an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group. ] 2. Hydroxymethyl-having the following general formula:
The biphenylcarboxylic acid ester derivative (II) was converted to [In the formula, R ² has the same meaning as described above. ] A method for producing a sulfonyloxy-biphenylcarboxylic acid ester derivative (I), which comprises sulfonylation. 3. Hydroxymethyl-having the following general formula:
The biphenylcarboxylic acid derivative (III) was converted to A process for producing a sulfonyloxy-biphenylcarboxylic acid ester derivative (I), which comprises esterifying to give a hydroxymethyl-biphenylcarboxylic acid ester derivative (II) and further sulfonylating. 4. Hydroxymethyl-having the following general formula:
The biphenyloxazoline derivative (IV) was converted to A deprotecting group to give a hydroxymethyl-biphenylcarboxylic acid derivative (III), and then esterification to give a hydroxymethyl-biphenylcarboxylic acid ester derivative (II),
A method for producing a sulfonyloxy-biphenylcarboxylic acid ester derivative (I), which comprises further sulfonylation. 5. Alkoxymethyl-having the following general formula:
The biphenyloxazoline derivative (V) was converted to [Wherein R ³ is a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group, a cycloether group, a trialkylsilyl group, a triarylsilyl group, a lower alkyl group, a vinyl group, an aralkyl group or It means a triphenylmethyl group. ] Deprotection group to hydroxymethyl-biphenyloxazoline derivative (IV), then deprotection group to hydroxymethyl-biphenylcarboxylic acid derivative (III),
Then, a method for producing a sulfonyloxy-biphenylcarboxylic acid ester derivative (I), which comprises esterifying to form a hydroxymethyl-biphenylcarboxylic acid ester derivative (II) and further sulfonylating. 6. A 4-bromobenzyl ether derivative (VI) having the following general formula: [Wherein R ³ has the same meaning as described above. ] Coupling with oxazolylanisole by Grignard reaction to alkoxymethyl-biphenyloxazoline derivative (V), then deprotecting group to hydroxymethyl-biphenyloxazoline derivative (IV), and then deprotecting group to hydroxymethyl-biphenyloxazoline derivative (IV) A process for producing a sulfonyloxy-biphenylcarboxylic acid ester derivative (I), which comprises converting the compound to a biphenylcarboxylic acid derivative (III), then esterifying the compound to a hydroxymethyl-biphenylcarboxylic acid ester derivative (II), and further sulfonylating the compound. 7. A 4-bromobenzyl ether derivative (VI) is protected by protecting 4-bromobenzyl alcohol, and then coupled with an oxazolylanisole by a Grineer reaction to give an alkoxymethyl-biphenyloxazoline derivative (V). As a deprotecting group, hydroxymethyl-
Biphenyl oxazoline derivative (IV), followed by deprotection to give hydroxymethyl-biphenylcarboxylic acid derivative
(III) and then esterified to give hydroxymethyl-
Biphenylcarboxylic acid ester derivative (II), which is further sulfonylated
Process for producing biphenylcarboxylic acid ester derivative (I). 8. A carboxy-biphenyloxazoline derivative (VII) having the following general formula: Alternatively, an alkoxycarbonyl-biphenyloxazoline derivative (VIII) having the following general formula is [Wherein R ⁴ is a lower alkyl group, an aryl group, an aralkyl group, a cycloether group, a trialkylsilyl group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, or thioalkoxy. It means an alkyl group or a triphenylmethyl group. ] Hydroxymethyl-biphenyloxazoline derivative (IV) is reduced with a metal-hydrogen complex compound, and then deprotecting group is converted to hydroxymethyl-biphenylcarboxylic acid derivative (III), and then esterified to give hydroxymethyl-biphenylcarboxylic acid ester derivative
(II), further sulfonylated, sulfonyloxy-biphenylcarboxylic acid ester derivative
The manufacturing method of (I). 9. A carboxy-biphenyloxazoline derivative (VII) having the following general formula is esterified with a lower alcohol to give an alkoxycarbonyl-biphenyloxazoline derivative (VIII), which is then reduced with a metal-hydrogen complex compound to give hydroxymethyl-biphenyloxazoline. Derivative
(IV), followed by deprotection to give a hydroxymethyl-biphenylcarboxylic acid derivative (III), then esterification to give a hydroxymethyl-biphenylcarboxylic acid ester derivative (II), and further sulfonylation Process for producing oxy-biphenylcarboxylic acid ester derivative (I). 10. A methyl-biphenyloxazoline derivative (IX) having the following general formula: It is oxidized with an oxidizing agent to give a carboxy-biphenyloxazoline derivative (VII) and then esterified with a lower alcohol to give an alkoxycarbonyl-biphenyloxazoline derivative (VIII) which is reduced with a metal hydrogen complex compound or immediately reduced with a metal hydrogen complex compound. To form a hydroxymethyl-biphenyloxazoline derivative (IV), and then deprotecting the hydroxymethyl-biphenylcarboxylic acid derivative (I).
II), followed by esterification to form a hydroxymethyl-biphenylcarboxylic acid ester derivative (II), and further sulfonylation. A process for producing a sulfonyloxy-biphenylcarboxylic acid ester derivative (I). 11. A 4-hydroxymethyl-biphenylcarboxylic acid derivative (X) having the following general formula. [Chemical 10] [Wherein R ⁵ is a hydrogen atom, a lower alkyl group, an aryl group,
It means an aralkyl group, a cycloether group, a trialkylsilyl group, a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethyl group. ]