JPH0616641A - Quinolin-2-ylbenzoic acid derivative and its production - Google Patents

Abstract

PURPOSE:To obtain a new quinolin-2-ylbenzoic acid derivative useful as an intermediate for angiotensin II antagonistic agents having quinoline ring. CONSTITUTION:The compound of formula I [R<1> to R<6> are H, halogen, lower alkyl, alkoxyl or halogen-substituted lower alkyl; R<7> is COOR<8> (R<8> is H, lower alkyl, alkenyl, cyclo-lower alkyl, aryl or aralkyl)], e.g. 2-(2-carboxyphenyl)-6- methyl-4-quinolinecarboxylic acid. The compound of formula I in which R<8> is a group other than H is obtained by reacting isatins of formula II with acetylbenzoic acids of formula III, selectively protecting the carboxyl group on the benzene ring of the resultant carboxyphenylquinolinecarboxylic acids of formula IV and then decarboxylating the carboxyl group on the quinoline ring.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a process for producing a quinolin-2-ylbenzoic acid derivative useful as an intermediate raw material for an angiotensin II antagonist, which is a promising therapeutic agent for hypertension.

[0002]

2. Description of the Related Art The blood pressure of a living body is regulated by the sympathetic nervous system or the balance between the pressure-increasing system and the pressure-increasing system. The renin-angiotensin system is involved in the pressor system. Renin acts on angiotensinogen to produce angiotensin I. Angiotensin I is further converted to angiotensin II by an angiotensin converting enzyme. Angiotensin II has a strong vasoconstrictor action, and also acts on the adrenal cortex to promote the secretion of aldosterone, resulting in an increase in blood pressure. Since angiotensin II acts through the angiotensin II receptor on the cell membrane, its antagonist is similar to an angiotensin-converting enzyme inhibitor.
It can be used as a remedy for hypertension caused by II.

Up to now, peptidic angiotensin II antagonists represented by salaracin have been known, but it is known that they are not effective in oral administration because they are peptidic. Recently, non-peptide angiotensin II antagonists have been reported (for example, JP-A-56-7107).
No. 4, Japanese Patent Publication No. 3-501020, etc.), and it has been confirmed to be effective by oral administration.

The present inventors have intensively searched for a non-peptidic compound having an angiotensin II antagonistic effect and effective in oral administration, and as a result, found that a novel quinoline derivative is effective. The novel quinoline derivative is, for example, a compound having a quinoline ring represented by the general formula (1) described below, which has a methylene group at the position of R ² (1
There is a compound having a (H-imidazol-1-yl) skeleton or a (3H-imidazo [4,5-b] pyridin-3-yl) skeleton bonded thereto. Further, in such a quinoline derivative, a compound in which a C-bonded tetrazolyl group is bonded instead of R ⁷ is also useful as a compound having an angiotensin II antagonistic activity. The present invention relates to a quinolin-2-ylbenzoic acid derivative which is a synthetic intermediate of this novel quinoline derivative.

The present invention is also an invention relating to a method for producing the above-mentioned quinolin-2-ylbenzoic acid derivative.

As known as an example of synthesizing a quinolin-2-ylbenzoic acid derivative, it has been known that n-butyllithium is allowed to act on 2-bromoquinoline to give a thio compound as shown in the following reaction formula, and a dialkyl compound is obtained. After conversion to quinolinyl borane, it is reacted with methyl o-bromobenzoate in the coexistence of KOH, tetrabutylammonium bromide and a zero-valent palladium catalyst to synthesize methyl 2- (2-quinolinyl) benzoate. Yes (M. Terashima et
al., Heterocycles, 23, 2375, (1985)).

[0007]

[Chemical 7]

In the previously known methods for synthesizing quinolin-2-ylbenzoic acid derivatives, it is necessary to use an organolithium compound such as n-butyllithium in order to introduce a substituent at the 2-position of the quinoline ring. However, this is not an advantage in industrial production. Further, in this synthetic method, the quinolin-2-ylbenzoic acid derivative having a substituent is scarcely known so far because it is restricted by the substituent on the quinoline ring. The manufacturing method of the present invention solves these conventional problems.

[0009]

The present invention provides the following inventions relating to the quinolin-2-ylbenzoic acid derivative, a method for producing the same, and carboxyphenylquinolinecarboxylic acids or their esters which are intermediates in the method for producing. is there. Quinoline-2 represented by the following general formula (1)
-Ilbenzoic acid derivative.

[0010]

[Chemical 8]

Isatins represented by the following general formula (2) and acetylbenzoic acids represented by the following general formula (3) are reacted to produce carboxyphenylquinolinecarboxylic acids represented by the following general formula (4). Then, after selectively protecting the carboxyl group on the benzene ring, the carboxyl group on the quinoline ring is decarboxylated, and the quinolin-2-ylbenzoic acid represented by the following general formula (1 ′) is characterized. Method for producing derivative.

[0012]

[Chemical 9]

[Chemical 10]

[Chemical 11]

[Chemical 12]

A compound comprising a carboxyphenylquinolinecarboxylic acid represented by the following general formula (4) or an ester thereof.

[0014]

[Chemical 13]

However, in the above general formula, R ¹ , R ² ,
R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁹ each independently represent the following. R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ : each independently a hydrogen atom, a halogen atom, a lower alkyl group, an alkoxyl group, or a halogen-substituted lower alkyl group. R ⁷ : -COOR ⁸ (wherein R ⁸ represents a hydrogen atom, a lower alkyl group, an alkenyl group, a cyclo lower alkyl group, an aryl group, or an aralkyl group). R ⁹ : -COOR ¹⁰ (wherein R ¹⁰ is a lower alkyl group,
Represents an alkenyl group, a cyclo-lower alkyl group, an aryl group or an aralkyl group).

In the above description and the following description of the present specification, the "lower" organic group means 1 to 6 carbon atoms. Suitable examples of "lower alkyl group" include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t-butyl group, pentyl group, hexyl group and the like. As the "alkenyl group", a lower alkenyl group is preferable, and an alkenyl group having 4 or less carbon atoms is particularly preferable. Suitable examples thereof are vinyl groups,
Examples thereof include allyl group, 1-propenyl group, 1-butenyl group and the like. Further, the "halogen atom" means a fluorine atom,
It means a chlorine atom, a bromine atom and an iodine atom. As the "halogen-substituted lower alkyl group", a lower alkyl group in which one or more fluorine atoms or chlorine atoms are substituted is preferable, and C _m F _{2m + 1} (m = 1 to 6) is particularly preferable.

The "alkoxyl group" is preferably a lower alkoxyl group, and particularly preferably an alkoxyl group having 4 or less carbon atoms. Suitable examples thereof include methoxy group, ethoxy group, propoxy group, butoxy group and the like.
The “cyclo lower alkyl group” means a cycloalkyl group having a ring carbon number of 3 to 6, and suitable examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like. The "aryl group" refers to a monovalent aromatic hydrocarbon group, preferably a phenyl group or a derivative thereof. Suitable examples thereof include phenyl group, tolyl group, p-halophenyl group and the like.
The "aralkyl group" means an aryl group-substituted alkyl group, and the alkyl group preferably has 4 or less carbon atoms. Suitable examples thereof include benzyl group, benzhydryl group,
Examples thereof include a trityl group and a phenethyl group.

In the quinolin-2-ylbenzoic acid derivative represented by the general formula (1), it is preferable that R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom or a lower alkyl group. A methyl group is preferred as the alkyl group. R ⁵ and R ⁶ are preferably each independently a hydrogen atom, a halogen atom, or a lower alkyl group, and the halogen atom is preferably a chlorine atom or a bromine atom. R ⁸ is preferably a hydrogen atom or a lower alkyl group. R ¹⁰ is preferably a lower alkyl group. Further, it is particularly preferable that R ⁷ is bonded to the ortho position of the benzene ring. Similarly, the carboxyl group in the general formulas (3) and (4), and the R in the general formula (1 ′)
It is particularly preferable that ^{9 is} also bonded to the ortho position of the benzene ring.

The isatins and acetylbenzoic acids used as raw materials in the production method of the present invention are commercially available or can be easily synthesized.

In order to produce a quinolin-2-ylbenzoic acid derivative by the production method of the present invention, first, isatins represented by the general formula (2) and a base such as sodium hydroxide or potassium hydroxide are stirred in water. Then, acetylbenzoic acids represented by the general formula (3) are added and heated. At this time, the base is 1 to 4 relative to acetylbenzoic acids.
The amount of acetylbenzoic acid used is 0.5 to 10 times mol, preferably 2 to 3 times mol,
The reaction is carried out at a reaction temperature of 50 ° C to reflux temperature, preferably 80 ° C to reflux temperature, using 0.5 to 2 times the molar amount. The reaction time is 0.5 to 10 hours, preferably 1 to 3 hours.

Then, the reaction mixture thus obtained is allowed to cool to room temperature, poured into ice-cold water, the aqueous layer is washed with a suitable organic solvent such as ether, and then acidified with dilute hydrochloric acid to obtain a precipitate. Is filtered to obtain carboxyphenylquinolinecarboxylic acids represented by the general formula (4).

Next, the carboxyl group on the benzene ring of the carboxyphenylquinolinecarboxylic acids represented by the general formula (4) is selectively protected. Esterification is preferable as the protection of the carboxyl group, but it is not limited thereto. In particular, it is preferable to protect with a lower alkyl ester. An example of protection by this esterification will be described below. Selective esterification of the carboxyl group on the benzene ring can be achieved by using the carboxyphenylquinolinecarboxylic acid
This can be easily done by simultaneously esterifying two carboxyl groups and then selectively hydrolyzing the ester group on the quinoline ring. Esterification is carried out with compounds which form R ⁹ , especially lower alkyl alcohols. This method is performed as follows, for example.

Carboxyphenylquinolinecarboxylic acids are suspended in an alcohol, for example methanol, and thionyl chloride is added under cooling. At this time, alcohol is 100 to 10 per mol of carboxyphenylquinolinecarboxylic acid.
000 ml, preferably 500 to 5000 ml, with a cooling temperature of -50 to
The temperature is 10 ° C, preferably -20 to 0 ° C. The obtained reaction mixture is stirred at 0 ° C. to reflux temperature, preferably room temperature to reflux temperature for 24 hours, concentrated under reduced pressure and purified to obtain a diester compound. To this, alcohol such as methanol and water is added, and 0.5 to 1.5 equivalents, preferably 1 equivalent of a base such as sodium hydroxide or potassium hydroxide is added and the mixture is added at 0 ° C to
Stir at reflux temperature, preferably room temperature to reflux temperature for 24 hours,
Concentration under reduced pressure gives a monoester compound in which the ester group on the quinoline ring is selectively hydrolyzed.

A suitable solvent such as diphenyl ether or "Dowtherm A" is added to the obtained monoester compound, and the temperature is 150 ° C to reflux temperature, preferably 180 ° C to 230 ° C.
For 5 minutes to 10 hours, preferably 5 minutes to 3 hours, to perform decarboxylation, allow to cool to room temperature, and then purify to purify the quinolin-2-ylbenzoic acid ester represented by the general formula (1 ′). Is obtained. Further, if this is hydrolyzed, quinolin-2-ylbenzoic acids represented by the general formula (1) in which R ⁷ is a carboxyl group can be obtained. The quinolin-2-ylbenzoic acids represented by the general formula (1 ′) are
The quinolin-2-ylbenzoic acids represented by the general formula (1) are those in which R ⁷ is not a carboxyl group (that is, R ⁸ is not a hydrogen atom).

The ester of carboxyphenylquinolinecarboxylic acid represented by the general formula (4) is preferably a lower alkyl diester or a lower alkyl monoester as described above, and as the monoester, only the carboxyl group on the benzene ring is used. Are preferably monoesters selectively esterified.

As described above, the quinolin-2-ylbenzoic acid represented by the general formula (1) of the present invention is useful as an intermediate of a compound having angiotensin II antagonistic activity. A compound having an angiotensin II antagonism is obtained by changing the substituents of the quinolin-2-ylbenzoic acids of the present invention, especially R ² to the heterocyclic skeleton-containing group as described above. Further, the compound of the present invention obtained by changing the substituent R ⁸ of the quinolin-2-ylbenzoic acid group to a C-bonded tetrazolyl group is also useful as an intermediate for a compound having an angiotensin II antagonistic action. This quinoline-2-of the present invention
It is easy to change the substituent R ⁷ of the ylbenzoic acid group to a C-bonded tetrazolyl group, for example, R ⁷ is —CONH
It can be changed to _two groups and then to a -CN residue, which in turn can be converted to a C-linked tetrazolyl group. Also,
A quinolin-2-ylbenzoic acid having a halogen atom, particularly a chlorine atom or a bromine atom, introduced at the 4-position of the quinoline ring is also useful as an intermediate for a compound having an angiotensin II antagonistic action.

The present invention will be described below with reference to examples.
The present invention is not limited to these examples.

[0028]

【Example】

 [Reference Example 1] 5-methylisatin

16.7 g (0.10 mol) of wrapped water chloral was added to water (222 m
l), add sodium sulfate (243 g), and p
-Toluidine 10.0g (93.3mmol) 4.4N hydrochloric acid solution (64m
l) and an aqueous solution (242 ml) of 20.5 g (0.29 mol) of hydroxylamine hydrochloride were added, and the mixture was heated under reflux for 30 minutes. After cooling to room temperature, the yellowish brown precipitate was collected by suction filtration. It was dissolved in 1.5N sodium hydroxide solution (500 ml) and neutralized with 2N hydrochloric acid. After filtering this, the filtrate was acidified with 2N hydrochloric acid. The precipitate was collected by filtration, washed with ice cold water and dried. The resulting isonitrosoacetanilide was added to concentrated sulfuric acid (62g) at 60 ° C for 4 hours.
It was added over 0 minutes and heated at 75 ° C. for 10 minutes. After cooling to room temperature, it was poured into ice-cold water (160 ml) and the precipitate was collected by filtration.
10.0 g of methyl isatin was obtained.

NMR (CD ₃ COCD ₃ ) δ = 9.9 (bs, 1H), 6.9-7.5 (m,
3H), 2.3 (s, 3H).

Reference Example 2 Isatin

33.4 g (0.20 mol) of wrapped water chloral was added to water (350 m
l), sodium sulfate (500 g) was added, and aniline 17.7 g (0.19 mol) in 4.4N hydrochloric acid solution (128 ml) and hydroxylamine hydrochloride 41 g (0.58 mol) in water (5
(00 ml) was added and the mixture was heated under reflux for 30 minutes. After cooling to room temperature, the yellowish brown precipitate was collected by suction filtration. It was dissolved in 1.5N sodium hydroxide solution (1000 ml) and neutralized with 2N hydrochloric acid. After filtering this, the filtrate was acidified with 2N hydrochloric acid. The precipitate was collected by filtration, washed with ice cold water and dried.

The obtained isonitrosoacetanilide was added to concentrated sulfuric acid (128 g) at 60 ° C. over 1 hour, and the mixture was further heated to 75 ° C.
Heated for 20 minutes. After cooling to room temperature, it was poured into ice-cold water (320 ml) and the precipitate was collected by filtration to obtain 18.3 g of isatin. _{NMR (CD 3 COCD 3) δ} = 9.9 (bs, 1H), 6.9-7.5 (m, 4H).

Reference Example 3 6-methylisatin

Using m-toluidine (9.3 g) in place of aniline in Reference Example 2 and performing the same operation, the reaction mixture was purified by silica gel column chromatography to obtain the title compound (3.2 g). NMR (CD ₃ COCD ₃ ) δ = 9.8 (bs, 1H), 7.0-7.5 (m, 3H), 2.4 (s, 3
H).

Reference Example 4 7-Methylisatin

Using the same procedure as in Reference Example 2 except that 20.0 g of o-toluidine was used instead of aniline, the title compound was obtained (15.3 g). NMR (CD ₃ COCD ₃ ) δ = 9.8 (bs, 1H), 7.0-7.5 (m, 3H), 2.6 (s, 3
H).

Example 1 2- (2-Carboxyphenyl) -6-methyl-4-quinolinecarboxylic acid

5-Methylisatin 5 produced in Reference Example 1
4.0 g (0.34 mol) and sodium hydroxide 40.2 g (1.0 mol) in water
(80 ml), followed by 55.0 g of 2-acetylbenzoic acid (0.
34 mol) was added and the mixture was heated under reflux for 2 hours. After allowing to cool to room temperature, it was poured into ice cold water (1 L). The aqueous layer was washed with ethyl acetate and then acidified with concentrated hydrochloric acid. The deposited precipitate is filtered and dried,
100.1 g of 2- (2-carboxyphenyl) -6-methyl-4-quinolinecarboxylic acid was obtained.

NMR (CD ₃ COCD ₃ ) δ = 7.70-8.70 (m, 8H), 2.66
(s, 3H).

Example 2 Methyl 2- (2-methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylate

2- (2-Carboxyphenyl) -6-methyl-4-quinolinecarboxylic acid prepared in Example 1 95.4
g (310 mmol) was suspended in methanol (720 ml). Thionyl chloride (46 ml, 620 mmol) was added thereto at -10 ° C, and the mixture was heated under reflux at 80 ° C for one day. After concentration under reduced pressure, the residue was diluted with dichloromethane (500 ml) and 2N aqueous sodium hydroxide solution (500
ml), the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from methanol and 2- (2-methoxycarbonylphenyl) -6-
83.4 g of methyl-4-quinolinecarboxylate was obtained.

NMR (CDCl ₃ ) δ = 7.5-8.6 (m, 8H), 4.0 (s, 3H),
3.6 (s, 3H), 2.6 (s, 3H).

Example 3 2- (2-Methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylic acid

30.4 g (90.6 mmol) of methyl 2- (2-methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylate prepared in Example 2 and 3.62 g of sodium hydroxide.
Dissolve (90.6mmol) in methanol (180ml) and water (180ml)
Was added and the mixture was stirred overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, water was added to the residue to make the aqueous layer alkaline, and then the aqueous layer was washed with ethyl acetate. The aqueous layer was acidified with 2N hydrochloric acid, and the solid precipitated upon standing was filtered and dried to give 2- (2-methoxycarbonylphenyl) -6-
11.3 g of methyl-4-quinolinecarboxylic acid was obtained.

NMR (CD ₃ COCD ₃ ) δ = 8.6-7.5 (m, 8H), 3.6 (s, 3
H), 2.6 (s, 3H).

Example 4 Methyl 2- (6-methylquinolin-2-yl) benzoate

15.2 g (42.2 mmol) of 2- (2-methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylic acid prepared in Example 3 was suspended in 47 ml of diphenyl ether and heated at 185 ° C. for 1.5 hours. After cooling to room temperature, the mixture was filtered, 2N hydrochloric acid was added to the filtrate for liquid separation, and the aqueous layer was separated with ethyl acetate (5
It was washed with 0 ml). The aqueous layer was neutralized with 2N aqueous sodium hydroxide solution, and the precipitated solid was collected by filtration and washed with water. The filter cake was recrystallized from methanol, and 2- (6-methylquinolin-2-yl) was used.
10.5 g of methyl benzoate was obtained.

NMR (CDCl ₃ ) δ = 7.4-8.1 (m, 9H), 3.6 (s, 3H),
2.5 (s, 3H).

Example 5 2- (6-Methylquinolin-2-yl) benzoic acid

7.08 g (25.5 mmol) of methyl 2- (6-methylquinolin-2-yl) benzoate prepared in Example 4 was suspended in 75 ml of methanol, and 3.06 g (76.6 mm) of sodium hydroxide was suspended.
ol) aqueous solution (35 ml) was added, and the mixture was heated at 60 ° C. for 3 hours.
After concentration under reduced pressure, water (200 ml) was added to the residue and acidified with 2N hydrochloric acid. The precipitated solid is collected by filtration, washed with water and dried to give 2- (6-
3.15 g of methylquinolin-2-yl) benzoic acid was obtained. NMR (CD ₃ OD) δ = 7.6-8.4 (m, 9H), 2.6 (s, 3H).

[Application Example 1] 2- (6-Methylquinolin-2-yl) benzamide 2- (6-methylquinolin-2-yl) benzoic acid prepared in Example 5 (2.47 g, 9.38 mmol) and toluene ( 30 ml) was added and suspended, and 1.37 ml (18.76 mmol) of thionyl chloride and N, N-dimethylformamide (0.02 ml) were added. The mixture was heated under reflux for 3 hours, allowed to cool to room temperature, and the solid was collected by filtration. Toluene from the filter cake
(10 ml), washed 3 times and dried. Concentrated aqueous ammonia (30 ml) was ice-cooled, and the solid obtained above was added to 1 with vigorous stirring.
It was added so as not to exceed 5 ° C. The mixture was stirred overnight at room temperature, water (30 ml) was added, and the solid was collected by filtration. The extract was washed 3 times with water (20 ml), the filter cake was suspended in diethyl ether, collected by filtration and dried to obtain 2.05 g of 2- (6-methylquinolin-2-yl) benzamide.

NMR (CDCl ₃ ) δ = 7.5-8.2 (m, 9H), 6.4 (bs, 1H),
5.6 (bs, 1H), 2.6 (s, 3H).

[Application Example 2] 2- (6-methylquinolin-2-yl) benzonitrile

Pyridine (15 ml) was added to 2.05 g (7.82 mmol) of 2- (6-methylquinolin-2-yl) benzamide prepared in Application Example 1 and the mixture was stirred, and 1.49 g (7.82 mmol) of p-toluenesulfonyl chloride was added. Was added. After stirring at room temperature for 2 hours, the mixture was stirred at 40 ° C. for 2 hours. The reaction mixture was poured into water (30 ml), extracted with methylene chloride (50 ml) and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel chromatography using a mixed solvent of hexane / ethyl acetate (7: 1) to give 2- (6-methylquinoline-2-
Yield) 0.86 g of benzonitrile was obtained.

NMR (CDCl ₃ ) δ = 7.5-8.2 (m, 9H), 2.6 (s, 3H).

[Application Example 3] 5- [2- (6-methylquinolin-2-yl) phenyl] -2-triphenylmethyl-2H-tetrazole

Toluene (3.5 ml) was added to 855 mg (3.5 mmol) of 2- (6-methylquinolin-2-yl) benzonitrile prepared in Application Example 2 and the mixture was stirred, and sodium azide was further added.
0.24 g (3.68 mmol), tributyltin chloride 1 ml (3.83 mmol)
Was added and the mixture was heated under reflux for 45 hours. Allow to cool and dilute with toluene (7ml), then with stirring, 10m aqueous sodium hydroxide solution 0.4m
1 (4 mmol) and 1.01 g (3.61 mmol) of trityl chloride were added. After stirring at room temperature for 1.5 hours, hexane (15 ml) was added. The solid was collected by filtration, twice with water (10 ml) and methanol (5 ml).
It was washed 3 times. The filter cake was dried to obtain 1.36 g of 5- [2- (6-methylquinolin-2-yl) phenyl] -2-triphenylmethyl-2H-tetrazole.

NMR (CDCl ₃ ) δ = 6.8-8.1 (m, 24H), 2.54 (s, 3
H).

Example 6 2- (2-Carboxyphenyl) -4-quinolinecarboxylic acid

29.0 g (0.20 mo) of isatin produced in Reference Example 2
l) and sodium hydroxide (24 g, 0.6 mol) were suspended in water (48 ml), 2-acetylbenzoic acid (33.0 g, 0.20 mol) was added, and the mixture was heated under reflux for 2.5 hours. After cooling to room temperature, ice-cold water
It was poured into (600 ml). The aqueous layer was washed with ethyl acetate and then acidified with concentrated hydrochloric acid. The deposited precipitate was collected by filtration and dried to give 2- (2
-Carboxyphenyl) -4-quinolinecarboxylic acid 49.6
got g. _{NMR (CD 3 COCD 3) δ} = 7.70-8.70 (m, 9H).

Example 7 Methyl 2- (2-methoxycarbonylphenyl) -4-quinolinecarboxylate

2- (2-Carboxyphenyl) 4-quinolinecarboxylic acid prepared in Example 6 (45.3 g, 0.155 mol) was suspended in methanol (360 ml). Thionyl chloride here 23
ml (0.31 mol) was added at -10 ° C, and the mixture was heated under reflux at 80 ° C. After concentration under reduced pressure, the residue was diluted with dichloromethane (250
ml) and 2N aqueous sodium hydroxide solution (250 ml), the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from methanol to obtain methyl 2- (2-methoxycarbonylphenyl) -4-quinolinecarboxylate (47.2 g).

NMR (CDCl ₃ ) δ = 7.5-8.6 (m, 9H), 3.9 (s, 3H),
3.5 (s, 3H).

Example 8 2- (2-Methoxycarbonylphenyl) -4-quinolinecarboxylic acid

Methyl 2- (2-methoxycarbonylphenyl) -4-quinolinecarboxylate prepared in Example 7
2.0 g (0.10 mol) and 4.0 g (0.10 mol) of sodium hydroxide were dissolved in methanol (60 ml), water (60 ml) was added, and the mixture was stirred overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, water was added to the residue to make the aqueous layer alkaline, and then the aqueous layer was washed with ethyl acetate. 2- (2-methoxycarbonylphenyl) -4-quinolinecarboxylic acid 2 was obtained by acidifying the aqueous layer with 2N hydrochloric acid, and allowing the precipitated solid to be collected by filtration and dried.
Obtained 4.5 g.

NMR (CD ₃ COCD ₃ ) δ = 7.5-8.4 (m, 9H), 3.54 (s,
3H).

Example 9 Methyl 2- (quinolin-2-yl) benzoate

2- (2-methoxycarbonylphenyl) -4-quinolinecarboxylic acid prepared in Example 8 25.8 g (8
4.4 mmol) was suspended in 94 ml of diphenyl ether, and 185 ° C.
Heated at 2.0 hours. After cooling to room temperature, filter and filter the filtrate with 2N.
Hydrochloric acid was added for liquid separation, and the aqueous layer was washed with ethyl acetate (150 ml). The aqueous layer was neutralized with 2N aqueous sodium hydroxide solution, and the precipitated solid was collected by filtration and washed with water. The filter cake was recrystallized from methanol and methyl 2- (quinolin-2-yl) benzoate 15.5 g
Got

NMR (CDCl ₃ ) δ = 7.4-8.2 (m, 9H), 3.60 (s, 3
H).

Example 10 2- (2-Carboxyphenyl) -7-methyl-4-quinolinecarboxylic acid Instead of 5-methylisatin in Example 1, 6-methylisatin (80 g) prepared in Reference Example 3 was used. Using the same procedure, the title compound was obtained (122 g). NMR (CD ₃ COCD ₃ ) δ = 7.7
0-8.50 (m, 8H), 2.52 (s, 3H).

Example 11 Methyl 2- (2-methoxycarbonylphenyl) -7-methyl-4-quinolinecarboxylate

Instead of 2- (2-carboxyphenyl) -6-methyl-4-quinolinecarboxylic acid in Example 2, 2- (2-carboxyphenyl) -7-methyl-4-prepared in Example 10 was used. Using quinolinecarboxylic acid, the title compound was obtained by the same procedure (41.8 g). NMR (CDCl ₃ ) δ = 7.5-8.4 (m, 8H), 3.9 (s, 3H), 3.6 (s, 3H), 2.4
(s, 3H).

Example 12 2- (2-Methoxycarbonylphenyl) -7-methyl-4-quinolinecarboxylic acid

2- (2-Methoxycarbonylphenyl) -7-methyl-prepared in Example 11 instead of methyl 2- (2-methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylate in Example 3. Using methyl 4-quinolinecarboxylate and performing the same procedure, the title compound was obtained (20.8 g). NMR (CD ₃ COCD ₃ ) δ = 8.5-7.5 (m, 8H), 3.5 (s, 3H), 2.5 (s, 3
H).

Example 13 Methyl 2- (7-methylquinolin-2-yl) benzoate

2- (2-Methoxycarbonylphenyl) -7-methyl-4 prepared in Example 12 instead of 2- (2-methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylic acid in Example 4. Using quinolinecarboxylic acid, the title compound was obtained by the same procedure (14.3 g).
. _{NMR (CDCl 3) δ = 7.4-8.2} (m, 9H), 3.6 (s, 3H), 2.4 (s, 3H).

Example 14 2- (7-Methylquinolin-2-yl) benzoic acid

In Example 5, 2- (6-methylquinoline-
Using methyl 2- (7-methylquinolin-2-yl) benzoate produced in Example 13 instead of methyl 2-yl) benzoate, the title compound was obtained by the same operation (14.9
g). NMR (CD ₃ OD) δ = 7.7-8.4 (m, 9H), 2.5 (s, 3H).

Example 15 2- (2-Carboxyphenyl) -8-methyl-4-quinolinecarboxylic acid

In Example 1, the 7-methylisatin produced in Reference Example 4 (80 g) was used in place of 5-methylisatin, and the same procedure was performed to obtain the compound shown in the table (13.9 g). NMR (CD ₃ COCD ₃ ) δ = 7.70-8.50 (m, 8H), 2.45 (s, 3H).

Example 16 Methyl 2- (2-methoxycarbonylphenyl) -8-methyl-4-quinolinecarboxylate

2- (2-Carboxyphenyl) -8-methyl-4-prepared in Example 15 instead of 2- (2-carboxyphenyl) -6-methyl-4-quinolinecarboxylic acid in Example 2. Using quinolinecarboxylic acid, the title compound was obtained by the same procedure (9.8 g). NMR (CDCl ₃ ) δ = 7.4-8.4 (m, 8H), 3.9 (s, 3H), 3.5 (s, 3H), 2.4
(s, 3H).

Example 17 2- (2-Methoxycarbonylphenyl) -8-methyl-4-quinolinecarboxylic acid

2- (2-Methoxycarbonylphenyl) -8-methyl-prepared in Example 16 instead of methyl 2- (2-methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylate in Example 3. The same procedure was performed using methyl 4-quinolinecarboxylate to obtain the title compound (7.8 g). NMR (CD ₃ COCD ₃ ) δ = 8.5-7.5 (m, 8H), 3.6 (s, 3H), 2.5 (s, 3
H).

Example 18 Methyl 2- (8-methylquinolin-2-yl) benzoate

2- (2-Methoxycarbonylphenyl) -8-methyl-4 prepared in Example 17 instead of 2- (2-methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylic acid in Example 4. Using quinolinecarboxylic acid, the title compound was obtained by the same procedure (6.0 g). NMR (CDCl ₃ ) δ = 7.4-8.3 (m, 9H), 3.6 (s, 3H), 2.5 (s, 3H).

Example 19 2- (8-Methylquinolin-2-yl) benzoic acid

In Example 5, 2- (8-methylquinoline-
Using methyl 2- (8-methylquinolin-2-yl) benzoate produced in Example 18 instead of methyl 2-yl) benzoate, the title compound was obtained by the same operation (4.9
g). NMR (CD ₃ OD) δ = 7.5-8.4 (m, 9H), 2.5 (s, 3H).

Example 20 2- (4-Carboxyphenyl) -6-methyl-4-quinolinecarboxylic acid

In place of 2-acetylbenzoic acid in Example 1, 35.0 g of 4-acetylbenzoic acid was used, and by the same procedure, the title compound was obtained (48.3 g). NMR (CD ₃ COCD ₃ ) δ = 7.70-8.70 (m, 8H), 2.60 (s, 3H).

Example 21 Methyl 2- (4-methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylate

Instead of 2- (2-carboxyphenyl) -6-methyl-4-quinolinecarboxylic acid in Example 2, 2- (4-carboxyphenyl) -6-methyl-4-prepared in Example 20. Using quinolinecarboxylic acid, the title compound was obtained by the same procedure (39.8 g). NMR (CDCl ₃ ) δ = 7.4-8.6 (m, 8H), 3.9 (s, 3H), 3.5 (s, 3H), 2.5
(s, 3H).

Example 22 2- (4-Methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylic acid

Instead of methyl 2- (2-methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylate in Example 3, 2- (4-methoxycarbonylphenyl) -6-methyl prepared in Example 21 was used. Using methyl-4-quinolinecarboxylate and by the same procedure, the title compound was obtained (30.0 g). NMR (CD ₃ COCD ₃ ) δ = 8.6-7.4 (m, 8H), 3.8 (s, 3H), 2.5 (s, 3
H).

Example 23 Methyl 4- (6-methylquinolin-2-yl) benzoate

Instead of 2- (2-methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylic acid in Example 4, 2- (4-methoxycarbonylphenyl) -6-methyl-prepared in Example 22 was used. Using 4-quinolinecarboxylic acid and the same procedure, the title compound was obtained (24.4 g)
. _{NMR (CDCl 3) δ = 7.4-8.2} (m, 9H), 3.9 (s, 3H), 2.6 (s, 3H).

Example 24 2- (3-Carboxyphenyl) -6-methyl-4-quinolinecarboxylic acid

Using 3-acetylbenzoic acid in place of 2-acetylbenzoic acid in Example 1 and following the same procedure, the title compound was obtained (50.5 g). NMR (CD ₃ COCD ₃ ) δ = 7.6-8.7 (m, 8H), 2.5 (s, 3H).

Example 25 Methyl 2- (3-methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylate

Instead of 2- (2-carboxyphenyl) -6-methyl-4-quinolinecarboxylic acid in Example 2, 2- (3-carboxyphenyl) -6-methyl-4-prepared in Example 24. The title compound was obtained by the same procedure using quinolinecarboxylic acid (47.6 g). NMR (CDCl ₃ ) δ = 7.4-8.5 (m, 8H), 3.9 (s, 3H), 3.6 (s, 3H), 2.5
(s, 3H).

Example 26 2- (3-Methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylic acid

Instead of methyl 2- (2-methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylate in Example 3, 2- (3-methoxycarbonylphenyl) -6-methyl prepared in Example 25 was used. Using methyl-4-quinolinecarboxylate and by the same procedure, the title compound was obtained (39.8 g). NMR (CD ₃ COCD ₃ ) δ = 8.6-7.3 (m, 8H), 3.6 (s, 3H), 2.6 (s, 3
H).

Example 27 Methyl 3- (6-methylquinolin-2-yl) benzoate

Instead of 2- (2-methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylic acid in Example 4, 2- (3-methoxycarbonylphenyl) -6-methyl-prepared in Example 26 was used. Using 4-quinolinecarboxylic acid and the same procedure, the title compound was obtained (30.5 g)
. NMR (CDCl ₃ ) δ = 7.4-8.4 (m, 9H), 3.5 (s, 3H), 2.6 (s, 3H).

[Example 28] 2- (3-Chloro-2-carboxyphenyl) -6-methyl-4-quinolinecarboxylic acid Instead of 2-acetylbenzoic acid in Example 1, 3-chloro-2-acetyl was used. The title compound was obtained by the same procedure using benzoic acid (10.5 g). NMR (CD ₃ COCD ₃ ) δ = 7.6-8.7 (m, 7H), 2.6 (s, 3H).

Example 29 2- (3-chloro-2-methoxycarbonylphenyl)
Methyl -6-methyl-4-quinolinecarboxylate

Instead of 2- (2-carboxyphenyl) -6-methyl-4-quinolinecarboxylic acid in Example 2, 2- (3-chloro-2-carboxyphenyl) -6- prepared in Example 28. Using methyl-4-quinolinecarboxylic acid, the title compound was obtained by the same procedure (8.8 g). NMR (CDCl ₃ ) δ = 7.4-8.5 (m, 7H), 3.9 (s, 3H), 3.8 (s, 3H), 2.7
(s, 3H).

[Example 30] 2- (3-chloro-2-methoxycarbonylphenyl)
-6-methyl-4-quinolinecarboxylic acid

2- (3-Chloro-2-methoxycarbonylphenyl) prepared in Example 29 instead of methyl 2- (2-methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylate in Example 3. -6-methyl-4
Using methyl quinolinecarboxylate, the title compound was obtained by the same procedure (3.8 g). NMR (CD ₃ COCD ₃ ) δ = 8.7-7.3 (m, 7H), 3.7 (s, 3H), 2.6 (s, 3
H).

Example 31 Methyl 2-chloro-6- (6-methylquinolin-2-yl) benzoate

In place of 2- (2-methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylic acid in Example 4, 2- (3-chloro-2-) prepared in Example 30.
Using methoxycarbonylphenyl) -6-methyl-4-quinolinecarboxylic acid, the title compound was obtained by the same procedure (2.0 g). _{NMR (CDCl 3) δ = 7.4-8.6} (m, 8H), 3.7 (s, 3H), 2.5 (s, 3H).

[0113]

The quinolin-2-ylbenzoic acid derivative useful as an intermediate raw material of an angiotensin II antagonist, which is a promising therapeutic agent for hypertension, can be easily obtained with isatins and acetyls without complicated operations such as using an organolithium compound. It can be produced from benzoic acids.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Tomoko Ito 1150, Hazawa-machi, Kanagawa-ku, Yokohama, Kanagawa Prefecture Asahi Glass Co., Ltd. Central Research Laboratory (72) Inventor Yoshitomi Morisawa, 1150, Hazawa-machi, Kanagawa-ku, Yokohama, Asahi Glass Co., Ltd. Central Research Center

Claims (12)

[Claims] 1. A quinoline-2 represented by the following general formula (1):
-Ilbenzoic acid derivative. [Chemical 1] However, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are each independently a hydrogen atom, a halogen atom, a lower alkyl group, an alkoxyl group, or a halogen-substituted lower alkyl group, R
⁷ represents a -COOR ^8. R ⁸ represents a hydrogen atom, a lower alkyl group, an alkenyl group, a cyclo lower alkyl group, an aryl group, or an aralkyl group. 2. The derivative according to claim ¹ , wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom or a lower alkyl group. 3. The derivative according to claim 1, wherein R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, or a lower alkyl group. 4. The derivative according to claim 1, wherein R ⁸ is a hydrogen atom or a lower alkyl group. 5. The derivative according to claim 1, which is 2- (6-methylquinolin-2-yl) benzoic acid or a lower alkyl ester thereof. 6. A carboxyphenylquinolinecarboxylic acid represented by the following general formula (4) by reacting an isatin represented by the following general formula (2) with an acetylbenzoic acid represented by the following general formula (3). And then selectively protecting the carboxyl group on the benzene ring, followed by decarboxylation of the carboxyl group on the quinoline ring, the quinolin-2-yl represented by the following general formula (1 ′): Process for producing benzoic acid derivative. [Chemical 2] [Chemical 3] [Chemical 4] [Chemical 5] However, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are each independently a hydrogen atom, a halogen atom, a lower alkyl group, an alkoxyl group, or a halogen-substituted lower alkyl group, R
⁹ represents a -COOR ^10. R ¹⁰ represents a lower alkyl group, an alkenyl group, a cyclo lower alkyl group, an aryl group, or an aralkyl group. 7. R ¹ , R ² , R ³ , and R ⁴ each independently represent a hydrogen atom or a lower alkyl group, and R ⁵ and R ⁶ each independently represent a hydrogen atom, a halogen atom, or a lower alkyl group. , R ¹⁰ is a lower alkyl group.
Manufacturing method. 8. A method for selectively protecting a carboxyl group on a benzene ring of carboxyphenylquinolinecarboxylic acids represented by the general formula (4) by esterifying both of the two carboxyl groups of carboxyphenylquinolinecarboxylic acid, The production method according to claim 6, which is carried out by selectively hydrolyzing the ester on the quinoline ring. 9. The compound represented by the general formula (2) is 5-methylisatin, and the compound represented by the general formula (3) is 2.
-Acetylbenzoic acid, the compound represented by the general formula (4) is 2- (2-carboxyphenyl) -6-methyl-
The production method according to claim 6, wherein the compound is 4-quinolinecarboxylic acid, and the compound represented by the general formula (1 ′) is a lower alkyl 2- (6-methylquinolin-2-yl) benzoic acid. 10. A compound comprising a carboxyphenylquinolinecarboxylic acid represented by the following general formula (4) or an ester thereof. [Chemical 6] However, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, an alkoxyl group, or a halogen-substituted lower alkyl group. 11. R ¹ , R ² , R ³ , and R ⁴ are each independently a hydrogen atom or a lower alkyl group, and R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, or a lower alkyl group. The compound of claim 10. 12. 2- (2-Carboxyphenyl) -6-
11. The compound of claim 10, which is methyl-4-quinolinecarboxylic acid, its lower alkyl diester, or its lower alkyl monoester.