WO2009119086A1

WO2009119086A1 - Method for producing 9-hydroxymethyl-cyclohepta[b]pyridine-3-carboxylate ester derivative

Info

Publication number: WO2009119086A1
Application number: PCT/JP2009/001325
Authority: WO
Inventors: 真一風山; 和広上元
Original assignee: トーアエイヨー株式会社
Priority date: 2008-03-26
Filing date: 2009-03-25
Publication date: 2009-10-01
Also published as: JP5424272B2; JPWO2009119086A1

Abstract

Disclosed is a method for commercially producing a 9-hydroxymethyl-cyclohepta[b]pyridine-3-carboxylate ester derivative. Specifically disclosed is a method for producing a 9-hydroxymethyl-cyclohepta[b]pyridine-3-carboxylate ester derivative represented by formula (1), which is characterized by reducing an epoxy derivative represented by general formula (3). (In the formula (3), R1 represents a halogen atom, a lower alkyl group or a lower alkoxy group; and R2 represents a lower alkyl group.) (In the formula (1), R1 and R2 are as defined above.)

Description

Method for producing 9-hydroxymethyl-cyclohepta [b] pyridine-3-carboxylic acid ester derivative

The present invention relates to a method for producing an intermediate of a compound that exhibits an inhibitory action on Na ⁺ / H ⁺ exchange transporter (NHE) and is useful as a prophylactic / therapeutic agent for diseases caused by enhancement of Na ⁺ / H ⁺ exchange transport system About.

The following general formula (A)

(The symbols in the formula are based on the general formula (1) of Patent Document 1)
As disclosed in Patent Document 1 and the like, the compound represented by the formula has an inhibitory effect on Na ⁺ / H ⁺ exchange transporter (NHE) and has a reduced toxic effect on the central nervous system. Caused by various diseases caused by stimulation of NHE, such as hypertension, arrhythmia, angina pectoris, cardiac hypertrophy, diabetes, organ damage due to ischemia or ischemia reperfusion, cerebral ischemic damage, cell hyperproliferation It is extremely useful as a prophylactic / therapeutic agent for the following diseases or restenosis due to coronary artery thickening after percutaneous coronary angioplasty, diseases due to vascular endothelial cell disorders such as arteriosclerosis.
In the production of the compound (A), a 9-hydroxymethyl-cyclohepta [b] pyridine-3-carboxylic acid ester derivative represented by the following general formula (1) is an important intermediate.
International Publication No. 2006/088080 Pamphlet

However, the production method of the compound (1) disclosed in Patent Document 1 is disadvantageous as an industrial production method because it requires a sealed tube reaction, which requires special equipment. It was. Furthermore, the yield is extremely low, about 30 to 40%, and it was essential to improve the yield from an industrial viewpoint.

Therefore, an object of the present invention is to solve such problems and to provide an industrial production method for 9-hydroxymethyl-cyclohepta [b] pyridine-3-carboxylic acid ester derivatives.

As a result of intensive studies in view of the above problems, the present inventor produced a new epoxy derivative by using the compound (2) as a starting material and epoxidizing it, and reducing this epoxy derivative, the end of the epoxy ring 9-Hydroxymethyl-cyclohepta [b] pyridine-3-carboxylic acid can be opened regioselectively on the cycloheptapyridine ring side without opening the side, and can generate reaction by-products and the like efficiently. It has been found that ester derivatives can be produced. Furthermore, this reaction does not require special equipment such as a sealed tube device that generally needs to cope with high-temperature and high-pressure conditions, and can be carried out in a normal reaction device.

That is, the present invention provides the following general formula (3)

(Wherein R ¹ represents a halogen atom, a lower alkyl group or a lower alkoxy group, and R ² represents a lower alkyl group.)
Wherein the epoxy derivative represented by formula (1) is reduced.

(Wherein R ¹ and R ² have the same definitions as above)
A method for producing a 9-hydroxymethyl-cyclohepta [b] pyridine-3-carboxylic acid ester derivative represented by the formula:

Also, the present invention provides the following general formula (2)

(In the formula, R ¹ and R ² have the same definitions as above.)
The compound represented by the formula (3)

(In the formula, R ¹ and R ² have the same definitions as above.)
An epoxy derivative represented by the formula (1), which is then reduced:

Also, the present invention provides the following general formula (3)

(In the formula, R ¹ and R ² have the same definitions as above.)
The compound represented by these is provided.

According to the present invention, a 9-hydroxymethyl-cyclohepta [b] pyridine-3-carboxylic acid ester derivative can be obtained with high yield and high selectivity without requiring special equipment, which is extremely useful industrially. It is.

BEST MODE FOR CARRYING OUT THE INVENTION

In the formula, examples of the halogen atom represented by R ¹ include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In the formula, examples of the lower alkyl group represented by R ¹ and R ² include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group. 6 linear or branched alkyl groups. Of these, a methyl group or an ethyl group is preferable, and a methyl group is particularly preferable.

In the formula, the lower alkoxy group represented by R ¹ is a straight chain having 1 to 6 carbon atoms such as methoxy group, ethoxy group, propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group and the like. Or a branched alkoxy group is mentioned.
R ¹ and R ² are preferably a lower alkyl group, particularly preferably a methyl group.

The production process of the 9-hydroxymethyl-cyclohepta [b] pyridine-3-carboxylic acid ester derivative (1) of the present invention is as follows.

(Wherein R ¹ represents a halogen atom, a lower alkyl group or a lower alkoxy group, and R ² represents a lower alkyl group.)

That is, the compound (2) is obtained by epoxidizing the compound (2) to obtain an epoxy derivative (3), which is then reduced. Here, the epoxy derivative (3) is a novel compound and is useful as a production intermediate of the compound (1) of the present invention.

Compound (2), which is a starting material of the present invention, is a known compound. For example, 2-benzylidenecycloheptanone is formylated according to the method described in Patent Document 1 and then reacted with 3-aminocrotonate. It can be obtained from the resulting 9-position benzylidene derivative by oxidative cleavage using potassium permanganate or the like. Furthermore, US Pat. Org. Chem. 49 (12), 2208-2212 (1984).
Hereinafter, it demonstrates in detail for every process.

Step 1 is a step of obtaining an epoxy derivative (3) by epoxidizing the compound (2). For the epoxidation reaction, a known method of reacting with a carbonyl group to synthesize oxirane can be used. For example, in the presence of a base, trimethylsulfoxonium salt, trimethylsulfonium salt, dimethylsulfonium methylide, dimethylsulfoxonium methyl It is carried out by reacting sulfur ylide prepared from Lido or the like.

Here, examples of the trimethylsulfoxonium salt and the trimethylsulfonium salt include trimethylsulfoxonium or a halide of trimethylsulfonium, and trimethylsulfoxonium iodide is particularly preferable.
The amount of trimethylsulfoxonium salt used is 1.0 to 2.0 equivalents (molar ratio), preferably 1.3 equivalents (molar ratio), relative to compound (2).

Examples of the base used in the reaction include alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide; alkali metal hydrides such as sodium hydride, potassium hydride and lithium hydride; n-butyl Alkyl alkali metals such as lithium, methyllithium and n-hexyllithium; Alkali metal amides such as sodium amide, potassium amide, lithium diisopropylamide, lithium dicyclohexylamide and lithium hexamethyldisilazide; potassium tert-butoxide, sodium tert -Alkali metal alkoxides such as butoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide and the like. Of these, sodium hydride and potassium tert-butoxide are preferable.
The amount of the base used is 1.0 to 2.0 equivalents (molar ratio), preferably 1.2 equivalents (molar ratio), relative to compound (2) from the viewpoint of suppressing the formation of by-products. .

The reaction solvent may be any solvent that does not inhibit the epoxidation reaction. For example, ether solvents such as tetrahydrofuran (THF), methyl tert-butyl ether (MTBE), diethylene glycol dimethyl ether (diglyme); N, N-dimethylformamide (DMF) ), N, N-dimethylacetamide (DMAc), dimethylsulfoxide (DMSO), N, N′-dimethylpropyleneurea (DMPU), hexamethylphosphoric triamide (HMPA), nitrobenzene, acetonitrile and the like; Halogenated hydrocarbon solvents such as methylene chloride; aromatic hydrocarbon solvents such as toluene and xylene can be used, and these can be used alone or in combination. Of these, ether solvents and aprotic polar solvents are preferable from the viewpoint of promoting the reaction and increasing the yield, and THF, DMSO or a mixed solvent thereof is particularly preferable.

The reaction temperature in step 1 is preferably in the range of −30 ° C. to room temperature from the viewpoint of preventing the condensation of the reaction solution, and the reaction time is preferably from 5 minutes to prevent a decrease in the yield. 2 hours.
The epoxy derivative (3) thus obtained may be isolated and purified by a conventional method and subjected to the next step, but the reaction solution thus obtained is used as it is without any further purification operation. You may use for a process.

Step 2 is a step of obtaining the compound (1) of the present invention by reducing the epoxy derivative (3). Although a known reduction method can be applied to the reduction reaction, the reaction is difficult to proceed by reduction or catalytic reduction with an aluminum hydride complex compound, and a by-product is easily generated. The following reducing agents are preferably used. In particular, it is preferably carried out in the presence of a Lewis acid from the viewpoint of promoting the reaction.
Normally, the ring opening of the epoxy ring occurs on carbon with less steric hindrance, but reduction under specific conditions does not produce an epoxy-terminated ring-opened product, and the target product opened on the cycloheptapyridine ring side is Obtained in high yield.

Examples of the reducing agent used in the reaction include metal borohydride compounds such as sodium borohydride, lithium borohydride, calcium borohydride, zinc borohydride, magnesium borohydride, sodium cyanoborohydride; diborane, Examples thereof include borane derivatives such as borane-tetrahydrofuran complex, borane-dimethyl sulfide complex, borane-ammonia complex, borane-t-butylamine complex, borane-dimethylamine complex, and borane-pyridine complex. Of these, sodium borohydride, borane-tetrahydrofuran complex, and borane-dimethylsulfide complex are preferred because they are easy to handle and promote the reaction and increase the yield. Particularly, sodium borohydride and borane-dimethyl are preferable. Sulfide complexes are preferred.
The amount of the reducing agent to be used is 1.0 to 2.0 equivalents (molar ratio), preferably 1.2 equivalents (molar ratio), relative to compound (3).

Examples of the Lewis acid used in the reaction include metal halides such as tin tetrachloride, titanium tetrachloride, aluminum trichloride, and iron trichloride; boron trifluoride complexes such as boron trifluoride diethyl ether complex. Among these, a boron trifluoride complex is preferable and a boron trifluoride diethyl ether complex is particularly preferable because it is relatively inexpensive and accelerates the reaction to increase the yield.
The amount of Lewis acid used is 1.5 to 3.0 equivalents (molar ratio), preferably 2.2 equivalents (molar ratio), relative to compound (3) in terms of promoting the reaction and increasing the yield. It is.

The reaction solvent is not particularly limited as long as it does not affect the reaction. For example, ether solvents such as THF, MTBE, dimethoxyethane, 1,4-dioxane; DMF, DMAc, DMSO, DMPU, HMPA, nitrobenzene, acetonitrile, etc. Examples include aprotic polar solvents; halogenated hydrocarbon solvents such as methylene chloride; aromatic hydrocarbon solvents such as toluene and xylene. These can be used alone or in combination. Of these, ether solvents such as THF, dimethoxyethane, and 1,4-dioxane are preferable, and THF is particularly preferable from the viewpoint of promoting the reaction and suppressing the formation of by-products and increasing the yield.

The reaction temperature in step 2 is preferably in the range of −30 ° C. to room temperature from the viewpoint of suppressing the formation of by-products, and the reaction time is preferably 5 minutes to 2 hours from the viewpoint of reaction efficiency. is there.
In this step, the order of administration of the reagents is not particularly limited, and the reduction reaction can be promoted by adding in any order. However, from the viewpoint of suppressing the production of by-products and increasing the yield, It is desirable to add the compound (3) after generating.

The 9-hydroxymethyl-cyclohepta [b] pyridine-3-carboxylic acid ester derivative (1) thus obtained is obtained by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, filtration, crystallization, recrystallization. In addition, isolation and purification can be performed by using various types of chromatography.

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

[Reference Example 1] 2-methyl-9-oxo-6,7,8,9-tetrahydro-5H-cyclohepta [b] methyl pyridine-3-carboxylate (reference compound (2))
Purification to a solution of methyl 9- (E) -benzylidene-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta [b] methyl pyridine-3-carboxylate (61.5 g) in acetone (2.0 L) Water (1.0 L) and potassium permanganate (79.0 g) were added, and the mixture was stirred at room temperature for 4 hours. 1 mol / L sodium sulfite aqueous solution (20 mL) was added, concentrated sulfuric acid (110 mL) and 1 mol / L sodium sulfite aqueous solution (1.28 L) were added in an ice bath, and the mixture was stirred at room temperature for 1 hour. After neutralization by adding 12 mol / L aqueous sodium hydroxide solution (160 mL) in an ice bath, the solvent was distilled off under reduced pressure. Extraction was performed with ethyl acetate (800 mL × 2), and the organic layer was washed with 1 mol / L aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Hexane (200 mL) was added to the residue, and the mixture was stirred for 1.5 hours in an ice bath, and the precipitated crystals were collected by filtration. The crystals were washed with hexane (100 mL) and dried under reduced pressure to give the title compound (33.8 g, 72.4%) as a pale yellow powder.
¹ H-NMR (CDCl ₃ ) δ 8.07 (1H, s), 3.94 (3H, s), 2.93-2.89 (2H, m), 2.86 (3H, s), 2 81-2.77 (2H, m), 1.96-1.84 (4H, m);
MS (ESI) m / z 234 (M + H) ^<+> .

[Example 1] Methyl 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta [b] methyl pyridine-9-spiro-2'-oxirane-3-carboxylate (compound (3) of the present application)
Under an argon atmosphere, potassium tert-butoxide (14.7 g) was added to a suspension of trimethylsulfoxonium iodide (28.6 g) in DMSO (40 mL), and the mixture was stirred at room temperature for 30 minutes. Further, THF (160 mL) was added, a solution of Reference Compound (2) (23.3 g) in THF (200 mL) was added at −20 ° C., and the mixture was stirred at the same temperature for 1 hour. Diisopropyl ether and ice water were added to separate the layers. The organic layer was washed with purified water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (22.2 g, 89.6%) as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ 7.93 (1H, s), 3.91 (3H, s), 3.28 (1H, d, J = 5.5 Hz), 3.09-3.00 ( 1H, m), 2.99 (1H, d, J = 5.5 Hz), 2.81-2.74 (1H, m), 2.77 (3H, s), 2.12-1.61 ( 6H, m);
MS (ESI) m / z 248 (M + H) ^<+> .

[Example 2] 9-hydroxymethyl-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta [b] methyl pyridine-3-carboxylate (compound (1) of the present application)
Under an argon atmosphere, boron trifluoride / diethyl ether complex (272 μL) was added to a suspension of sodium borohydride (45.4 mg) in THF (2 mL) in an ice bath, and the mixture was stirred at the same temperature for 10 min. In an ice bath, a solution of the present compound (3) (247 mg) in THF (2 mL) was added, and the mixture was stirred at the same temperature for 1 hour. Under an ice bath, 10 w / w% potassium carbonate aqueous solution and purified water were added, and the mixture was extracted with diisopropyl ether. The organic layer was washed with purified water and saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 10: 1-5). The title compound (216 mg, 86.6%) was obtained as a white powder by separation and purification in 1). The yield based on the reference compound (2) was as good as 77.6%.
¹ H-NMR (CDCl ₃ ) δ 7.93 (1H, s), 4.68 (1H, brs), 3.95 (2H, d, J = 2.5 Hz), 3.90 (3H, s) 3.15-3.08 (1H, m), 2.87-2.71 (2H, m), 2.78 (3H, s), 2.08-1.97 (2H, m), 1 .84-1.61 (2H, m), 1.43-1.21 (2H, m);
MS (ESI) m / z 250 (M + H) ^<+> .

[Example 3] 9-Hydroxymethyl-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta [b] methyl pyridine-3-carboxylate (compound (1)) (another method)
Under an argon atmosphere, boron trifluoride diethyl ether complex (272 μL) and borane-dimethyl sulfide complex (114 μL) were added to a THF (4 mL) solution of the present compound (3) (247 mg) in an ice bath at the same temperature. Stir for minutes. Under an ice bath, 10 w / w% potassium carbonate aqueous solution was added, and the mixture was extracted with diisopropyl ether. The organic layer was washed with purified water and saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 10: 1-5). The title compound (229 mg, 92.0%) was obtained as a white powder by separation and purification in 1). The yield based on the reference compound (2) was as good as 82.4%.
[Device data is the same as in Example 2]

Claims

The following general formula (3)

(Wherein R 1 represents a halogen atom, a lower alkyl group or a lower alkoxy group, and R 2 represents a lower alkyl group.)
Wherein the epoxy derivative represented by formula (1) is reduced.

(Wherein R 1 and R 2 have the same definitions as above)
A process for producing a 9-hydroxymethyl-cyclohepta [b] pyridine-3-carboxylic acid ester derivative represented by the formula:
The production method according to claim 1, wherein the reduction reaction is carried out by allowing a reducing agent to act in the presence of a Lewis acid.
The production method according to claim 2, wherein the Lewis acid is a metal halide or a boron trifluoride complex.
The production method according to claim 2 or 3, wherein the reducing agent is a metal borohydride compound or a borane derivative.
The following general formula (2)

(Wherein R 1 represents a halogen atom, a lower alkyl group or a lower alkoxy group, and R 2 represents a lower alkyl group.)
The compound represented by the formula (3)
(In the formula, R 1 and R 2 have the same definitions as above.)
An epoxy derivative represented by the formula (1), which is then reduced:

(Wherein R 1 and R 2 have the same definitions as above)
A process for producing a 9-hydroxymethyl-cyclohepta [b] pyridine-3-carboxylic acid ester derivative represented by the formula:
The production method according to claim 5, wherein the epoxidation reaction is carried out by reacting sulfur ylide.
The production method according to claim 5 or 6, wherein the reduction reaction is carried out by allowing a reducing agent to act in the presence of a Lewis acid.
The production method according to claim 7, wherein the Lewis acid is a metal halide or a boron trifluoride complex.
The production method according to claim 7 or 8, wherein the reducing agent is a metal borohydride compound or a borane derivative.
The following general formula (3)

(Wherein R 1 represents a halogen atom, a lower alkyl group or a lower alkoxy group, and R 2 represents a lower alkyl group.)
A compound represented by