KR100219251B1 - Optically active 1,6-naphthyridine derivatives - Google Patents

Abstract

Novel (+)-optically active 1, 6-naphthyridine derivatives of the following structural formula (I) and methods for their preparation are disclosed.

[In the above formula, each of R ¹ and R ² is independently a hydrogen atom or a C _1-4 alkyl group, and * denotes an asymmetric carbon atom.]

Also disclosed are methods for preparing other derivatives from the optically active 1,6-naphthyridine derivatives of formula (I).

Description

Optically active 1,6-naphthyridine derivatives

The present invention utilizes diastereomeric salts from the (+)-optically active isomers of 1, 6-naphthyridine derivatives and the optically active isomer mixtures of 1,6-naphthyridine derivatives to the (+ )-A method for preparing optically active isomers. The invention also relates to a process for the preparation of other derivatives from said (+)-optically active isomers of 1,6-naphthyridine derivatives.

Japanese Patent Publication No. 61 (1986) -143382 discloses a 1,6-naphthyridine derivative of the following structural formula (II).

[Wherein R ₁ is an unsubstituted or substituted aromatic group or an unsubstituted or substituted heterocyclic aromatic group; R ₂ is a straight or branched C _1-4 alkyl group or benzyl group; R ₃ is a hydrogen atom, a straight or branched C _1-4 alkyl group or a straight or branched C _1-4 alkoxycarbonyl group; R ₄ is a straight or branched C _1-4 alkyl group; R ₅ is a carboxyl group or straight chain, C _{1 ~ 17} alkoxy group which may contain an oxygen atom, a sulfur atom or a nitrogen atom of a branched-chain or cyclic.]

The publication discloses that the 1,6-naphthyridine derivatives of formula (III) have an effect on the blood vessels, which are associated with diseases of the blood vessels in the cerebrum, heart, or the vicinity, such as myocardial ischemia, cerebral infarction, pulmonary thrombosis, arteriosclerosis and other parts of the stenosis. It is said to be useful. The publication also describes that the compounds of formula (II) have racemic variants but do not describe the action of the optically active isomers of the compounds and their preparation.

In addition, B. Koidl et al. (Naunyn-Schmiedeberg's Arch. Pharmol., 337, 447-453 (1988)) disclose a compound of formula (IIIa).

[Wherein i -Pr is an isopropyl group.]

This document is stronger in that the (+)-optically active isomer of the compound of formula (IIIa) is the action of a compound having structural formula (IIIa) on the potential difference of isolated cardiomyocytes compared to its (-)-optically active isomer. Is described.

Another document (DJ Dooley et al., J. Neurochem., 49, 900-904 (1987)) describes [3H] PN200-110 binding [receptor Binding; Brain] describes that the titer of the (+)-optically active isomer of the compound of formula (IIIa) is approximately 13 times that of its (-)-optically active isomer.

As mentioned above, it is known that in the physiological activity of the compound of formula (IIIa), the (+)-optically active isomer of the compound of formula (IIIa) is stronger than its (-)-optically active isomer. However, it is very difficult to optically decompose the racemic variant of the compound of formula (IIIa) to obtain the (+)-optically active isomer. For example, racemic variants of compounds having structural formula (IIIa) are difficult to decompose even when using an acidic optical resolver. In addition, industrially useful processes for preparing optically active isomers of the compounds of formula (IIIa) are not known.

In addition, J. kleinschroth et al., Xth Int Symp Med Chem (1988) also report that the (+)-optically active isomers of the compounds of the following structural formula (IV) have a variety of effects by oral administration, such as the persistence of hypotensive action and It is known that it is more effective than its negative (-)-optically active isomer in various actions such as calcium antagonism. Compounds of the following formula (IV) can be prepared from compounds of the following formula (I).

Japanese Patent Publication No. 60 (1985) -54385 discloses 1, 6-naphthyridine derivatives of the following structural formula (V):

[Wherein, R ¹¹ is a methyl group or an ethyl group, R ¹² is a C _1-6 alkyl group.]

The Singgi publication describes that the 1,6-naphthyridine derivatives of formula (V) have vascular angiogenesis and platelet aggregation-inhibitory actions and the derivatives are used particularly effectively as drugs for the treatment of vascular and capillary diseases of the brain or heart. .

The 1, 6-naphthyridine derivative includes two types of optical isomers, but the publication does not describe the optically active isomers of 1, 6-naphthyridine derivatives and their pharmacological effects.

It is noted that the present invention can synthesize compounds of the following formula (III) (including the above compounds of formula (IIIa)) from compounds of the following formula (I):

[Wherein, each of R ¹ , R ² and R ³ is independently a C _1-4 alkyl group.]

As a result, the present inventors have resolved the (+)-optically active isomer of the 1,6-naphthyridine derivative of the following structural formula (I) from a mixture of the optically active 1,6-naphthyridine derivative of the following structural formula (I) It was found that the (+)-optically active isomers of the compounds obtainable and from the obtained isomers also have the structure (III).

It is an object of the present invention to provide (+)-optically active isomers of the 1,6-naphthyridine derivatives of the formula (I).

Another object of the present invention is to provide the (+)-optically active isomer of 1, 6-naphthyridine derivative which is useful as a substance for preparing the (+)-optically active isomer of the compound of formula (III). It is to provide a method for effectively preparing from a mixture of optically active 1,6-naphthyridine derivatives.

The invention provides the (+)-optically active isomers of the 1, 6-naphthyridine derivatives of formula (I):

[In the above formula, each of R ¹ and R ² is independently a hydrogen atom or a C _1-4 alkyl group and the * symbol represents an asymmetric carbon atom.]

The invention also provides a process for the preparation of the (+)-optically active isomers of the 1, 6-naphthyridine derivatives which consist of the following steps.

(a) reacting (+)-optically active camphorsulfonic acid or derivatives thereof with a mixture of optically active 1,6-naphthyridine derivatives of formula (I):

[Wherein each of R ¹ and R ² are independently a hydrogen atom or a C _{1 ~ 4} alkyl group, those marked * represents an asymmetric carbon atom.]

(b) the two diastereomeric salts prepared in step (a) are separated using the difference in solubility of the salts in the solvent;

(c) The (+)-optically active isomer of the 1, 6-naphthyridine derivative from the diastereomer-salt precipitated in step (b).

According to the present invention, the C _1-4 alkylating agent is also reacted with the (+)-optically active isomer of the 1, 6-naphthyridine derivative of the following formula (I) to the 1, 6-naphthy of the formula (III) Provided is a process for the preparation of the (+)-optical active isomers of a ridine derivative.

[In the above formula, each of R ¹ and R ² is independently a C _1-4 alkyl group, and * denotes an asymmetric carbon atom.]

[Wherein, each of R ¹ , R ² and R ³ is independently a C _1-4 alkyl group and the * symbol represents an asymmetric carbon atom.]

The present invention relates to the (+)-optically active isomer of the 1, 6-naphthyridine derivative of the above-mentioned structural formula (I).

In formula (I), each of R ¹ and R ² is independently a hydrogen atom or a C _1-4 alkyl group such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group or t-butyl group. Preferably, each of R ¹ and R ² is independently a methyl group or an ethyl group.

The (+)-optically active isomer of the 1, 6-naphthyridine derivative of formula (I) is a mixture of the optically active 1, 6-naphthyridine derivative of formula (I) and the (+)-optically active camphorsulfonic acid or derivatives thereof. The two diastereomeric salts prepared in the reaction step are separated using the solubility difference of the salts in the solvent, and the (+) of the 1, 6-naphthyridine derivative from the diastereomeric salt precipitated in the separation step. Obtainable by isolating optically active isomers.

The mixture of optically active 1, 6-naphthyridine derivatives of formula (I) may be racemic variants or residues obtained by removing a portion of the optically active isomers of 1, 6-naphthyridine derivatives from said racemic variants ( +)-Isomer and residual (-)-may be a mixture of isomers.

Racemic variants of the 1,6-naphthyridine derivatives can be prepared, for example, according to the method described in Japanese Patent Publication No. 60 (1985) -54385.

For example, it can be prepared by reacting 1,3,5-triazine with 1,4-dihydropyridine derivative of the following structural formula (VI) in the presence of a base.

[Wherein, R ¹ and R ² have the same meaning as described above.]

Examples of (+)-optically active camphorsulfonic acid or derivatives thereof that can be used as an optically dissolving agent in the decomposition process include: (+)-optically active camphor-10-sulfonic acid, (+)-optically active camphor-8-sulfonic acid and (+)-Halides of optically active camphorsulfonic acid on ring-forming carbon atoms (eg bromide and chloride thereof). Preferably, it is (+)-3-bromocamphor-10-sulfonic acid.

There is no particular limitation on the ratio of the optically active 1, 6-naphthyridine derivatives of the formula (I) and the ratio of the optically decomposing agent, but the optically decomposing agent is the (+)-optical Preference is given to using 1 to 2 molar amounts per mole of active isomer.

In the process of the invention, the reaction product of the (+)-optically active isomer and (+)-optically active camphorsulfonic acid or derivatives thereof of the 1, 6-naphthyridine derivative of formula (I) is half Precipitated into crystals in solution and the crystals are isolated from the (-)-optically active isomer of the 1,6-naphthyridine derivative which is still dissolved in the reaction solution.

Thus, in the process of the invention, the mixture of optically active 1, 6-naphthyridine derivatives of formula (I) is optical in a solvent in which the difference in solubility between the two diastereomeric salts prepared in the reaction step can be seen. Reacted with a disintegrant. Examples of solvents include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, acetone, methylethylketone, acetonitrile, ethyl acetate, butylacetate, dioxane and THF (tetrahydrofuran) do. These solvents may be used alone or in combination. Also mixtures of water and these solvents can be used. Especially preferred are ethanol and 2-propanol.

According to the present invention, the mixture of optically active 1,6-naphthyridine derivatives is reacted with an optical dissolving agent as described above, and if necessary, after further solvent is added to the reaction solution, the reaction solution is cooled and until crystals are sufficiently precipitated. Maintain at the predetermined temperature. In this step, the reaction solution can be stirred if necessary. To further accelerate the precipitation of the crystals, a small amount of salt, which is the same salt as the diastereomeric salt to be precipitated in the reaction solution, can be added as seed. Conditions of decomposition, such as the type and composition of the solvent, the concentration of solids and the temperature and time required for crystal precipitation, are suitable to increase the purity of the (+)-optically active isomer of the 1,6-naphthyridine derivative as high as possible. Decide on Determination of the above conditions can be easily made by those skilled in the art.

The precipitated diastereomeric salt is collected by filtration. If desired, the collected diastereomeric salts can be partially dissolved or recrystallized in the same solvent used to prepare the diastereomeric salts. Thus, purified diastereomeric salts can be obtained.

The purified diastereomeric salts obtained are then reacted with bases such as sodium carbonate, sodium hydroxide, potassium carbonate and potassium hydroxide to separate the diastereomeric salts to yield 1, 6-(+)-optically active isomers of naphthyridine derivatives are obtained.

If desired, the (+)-optically active isomers of the 1,6-naphthyridine derivatives of formula (I) may be added salts of inorganic acids (eg hydrochloric acid, sulfuric acid and phosphoric acid) or organic acids (eg acetic acid, propionic acid, citric acid) And pharmacologically acceptable salts such as addition salts of tartaric acid, malic acid, oxalic acid and methanesulfonic acid.

As a mixture of the optically active 1, 6-naphthyridine derivative of the structural formula (I) which is a starting material used in the preparation method of the optically active isomer of the structural formula (I), the 1,6-naphthyridine derivative of the structural formula (I) Racemic variants of can be used. Also mixtures of (+)-optically active isomers and (-)-optically active isomers can be used, which can be used to convert racemic variants of the 1, 6-naphthyridine derivatives of formula (I) according to the diastereomeric salt method Obtained by decomposing the racemic variant of the 1, 6-naphthyridine derivative of (I) and removing the (-)-optically active isomeric moiety to have a relatively high content of (+)-optical isomer. In the process of the present invention, this mixture can be easily used as starting molar to obtain the positive optically active isomer having high optical activity.

The optical isomer of the compound of formula (III) is prepared by alkylating the (+)-optically active isomer of 1, 6-naphthyridine derivative of formula (I) by a known method (e.g., using an alkylating agent). Easy to obtain.

Examples of alkylating agents that can be used in the present invention include alkyl halides (eg, alkyl chlorides, alkyl bromides and alkyl iodides), ilkylsulfonates, alkyl sulfates and trialkyloxonium salts. Examples of the alkyl group included in the alkylating agent are C _1-4 alkyl groups, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl.

In the case of using an alkyl halide as the alkylating agent, the (+)-isomer of the 1,6-naphthyridine derivative of the formula (I) is converted to a base such as a carbonate, hydride or alkoxide of a metal (alkali or alkaline earth metal). It is preferred to react in the presence of a suitable solvent.

The alkylation reaction is generally carried out in a suitable solvent, and various solvents may be used as the solvent. Preferred examples of the solvent include bicyclic, cyclic or aromatic hydrocarbons such as n-pentane, n-hexane, cyclohexane, benzene and toluene; Halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane; Ethers such as diethyl ether and 1,2-dimethoxyethane; And polar neutral solvents such as dimethylformamide, hexamethylphosphoric triamide and dimethyl sulfoxide.

The alkylation reaction is generally carried out at room temperature to the boiling point of the solvent used, preferably under an inert gas atmosphere such as a nitrogen gas atmosphere.

After the reaction is completed, the (+)-optically active isomer of the 1, 6-naphthyridine derivative of the obtained formula (III) is purified from a suitable solvent by a method such as extraction, recrystallization and the like. Therefore, the (+)-optically active isomer of the 1, 6-naphthyridine derivative of the formula (III) can be obtained in high yield.

If the salt of the target compound is formed by adding an appropriate inorganic acid (e.g. hydrochloric acid, sulfuric acid or phosphoric acid or organic sulfonic acid to the reaction solution separation step) to obtain the target compound, the reaction solution can be easily separated to obtain the target compound. Sulfates of the desired compound are preferred The salts of the desired compound are treated in a purification step with an appropriate alkali to give the isomers of the desired compound.

The (+) optically active isomers of the 1,6-naphthyridine derivatives of formula (III) prepared by the process of the present invention may be added to the addition salts of organic acids (eg hydrochloric acid, sulfuric acid and phosphoric acid) or organic acids (eg, Pharmaceutically acceptable salts such as addition salts of acetic acid, propionic acid, citric acid, tartaric acid, malic acid, oxalic acid, and metasulfonic acid).

The invention is further described by the following examples.

Reference Example 1

(±)-1, 4, 5, 6-tetrahydro-2-methyl-5-oxo-4-(2-trifluoromethylphenyl)-1, 6-naphthyridine-3-carboxylic acid ethyl ester (±)-referred to as ester A].

39.7 g (0.10 mol) of 1,4-dihydro-2,6-dimethyl- 4-(2-trifluoromethylphenyl) pyridine in 200 mL of anhydrous N, N-dimethylformamide (DMF) A solution of dicarboxylic acid diethyl ester is added to a suspension containing 4.00 g (0.10 mol) of 60% sodium hydride in 50 mL of anhydrous DMF over 45 minutes with stirring under a nitrogen atmosphere. After the hydrogen has separated, the reaction mixture is stirred for a further 15 minutes. To the reaction mixture is added dropwise a solution containing 8.11 g (0.10 mol) of 1, 3, 5-triazine in 150 ml of DMF and the resulting reaction mixture is heated at 110 ° C. for 16 hours. DMF is removed from the reaction mixture under reduced pressure. 750 ml of acetone is added to the residue and stirred. The resulting mixture is then filtered to separate insolubles. The resulting filtrate is concentrated under reduced pressure and the tar-like residual acid is dissolved in 415 ml of methanol while heating. The obtained solution is cooled to room temperature to precipitate crystals. The precipitated crystals were collected by filtration and the collected crystals were washed to give (±)-crude crystalline methanol of ester A-single molecule addition product (amount: 23.0 g).

In addition, the obtained crude product is purified by silica gel-column chromatography and then recrystallized from ethanol to give (±)-purified crystalline ethanol-single molecule addition product of ester A.

Example 1

(+) -1,4,5,6 -tetrahydro-2 -methyl-5 -oxo-4-(2-trifluoromethylphenyl) -1,6-naphthyridine-3 -carboxylic acid ethyl ester (+)-Referred to as ester A].

4.46 g (10.5 mmol) of (±) -1 purified ethanol-molecular addition product of ester A and 2.44 g (10.5 mmol) of (S)-(+)-obtained in 210 mL of ethanol in Reference Example 1 Camphor-10 sulfonic acid is added while heating. Seed crystals are added to the resulting solution and allowed to stand overnight at room temperature. The precipitated crystals are collected by filtration and the collected crystals are washed with ethanol and dried to yield 2.53 g of crude diastereomer salt. 2.41 g of this crude diastereomeric salt (crystal form) is dissolved in 70 ml of ethynol while heating and the resulting solution is left overnight at room temperature. The precipitated crystals are collected by filtration and the collected crystals are washed with ethanol and dried to yield 2.02 g of purified diastereomeric salt.

The obtained crystals are suspended in a mixture of 60 ml of methylene chloride and 50 ml of water. 10 ml of 10% aqueous NaOH solution is added to the resulting suspension and stirred for 30 minutes at room temperature. The suspension is then filtered to collect insoluble crystals and the collected crystals are washed with water to yield 0.26 g of (+)-ester A as a crystalline white powder.

In addition, a methylene chloride layer is separated from the filtrate obtained by the above filtration. The layer is washed with water then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.94 g of (+)-ester A white powder.

[a] _D ²³ : + 77.6 ° (c 0.499, methanol) ¹ H NMR (DMSO-d ₆ ) δ:

1.12 (3H, t, J = 7 Hz), 2.29 (3H, s), 3.5 to 4.2 (2H, m)

5.52 (1H, s), 5.87 (1H, d, J = 7 Hz)

7.09 (1h, d, J = 7 Hz), 7.0 to 7.5 (4H, m)

9.12 (1 H, br, s), 10.72 (1 H, br.S) IR (KBr) cm ⁻¹ :

3700-2400, 1660, 1620, 1580, 1495, 1465, 1445, 1310, 1250, 1205, 1150, 1100, 1030, 760.

Example 2

(+)-Ester A

212 mg (0.501 mmol) of (±) -purified ethanol-ester molecule addition product of ester A and 165 mg (0.501 mmol) of (S)-(+)-3 in 12 ml of ethanol Bromocamphor 10 Sulphonic acid monohydrate is dissolved while heating. The resulting solution is left at room temperature overnight. The precipitated crystals are collected by filtration to yield 110 mg of crude diastereomer-salt. 100 mg of crude diastereomeric salt is suspended in a mixture of 20 ml of methylene chloride and 5 ml of water. 1 ml of 10% aqueous NaOH solution is added to the resulting suspension and stirred for 30 minutes at room temperature. The methylene chloride layer is then separated from the suspension. The layer was washed with water, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 55 mg of (+)-ester A as a white powder.

[α] _D ²³ : + 71.8 ° (c 0.550, methanol)

Example 3

(+)-Ester A

(±)-crude methanol of ester A-monomolecular addition product and 16.25 g (70.0 mmol) of (S)-obtained in the same manner as described in Reference Example A of 28.73 g (70.0 mmol) in 410 mL of ethanol (+)-Camphor-10-Sulphonic acid is dissolved while heating. Seed crystals are added to the resulting solution and allowed to stand overnight at room temperature. The precipitated crystals are collected by filtration and the collected crystals are washed with ethanol to yield 18.4 g of crude diastereomeric salts. The crude diastereomeric salt (crystal form) is dissolved in 500 ml of ethanol while heating and the resulting solution is left overnight at room temperature. The precipitated crystals are collected by filtration and the collected crystals are washed with ethanol to yield 16.48 g of white crystalline diastereomeric salts.

The obtained crystals are suspended in 50 ml 10% NaOH aqueous solution and the resulting suspension is thoroughly stirred for 30 minutes at room temperature. The suspension is then filtered to collect insoluble crystals and the collected crystals are washed with water to yield 9.08 g of (+)-ester A as crystalline white powder.

[α] _D ²³ : + 75.9 ° (c 0.519, methanol)

High performance liquid chromatography using a column of a silica gel filler (Daicel, Ltd., trade name: CHIRALCEL OF) obtained from the obtained (+)-ester A with tris (4-chlorophenylcarbamate) derivative of cellulose HPLC) to measure the optical purity.

Column: CHIRALCEL OF, 4.6 x 250mm

Mobile phase: Hexane / 2-propanol (6/1)

Flow rate: 0.5 ml / min

Column temperature: room temperature

Detection: UV 254 nm.

The optically active isomer of ester A is isolated completely under the above-mentioned conditions, and the optical purity of the (+)-isomer obtained in Example 3 is 99% or more.

Example 4

(+)-Ester A

(±)-crude methanol of single ester-monomolecular addition salt and 5.332 g (21.30 mmol) of (S) obtained in the same manner as described in Reference Example 1 of 8.742 g (21.30 mmol) in 35 ml of 2-propanol. )-(+)-Camphor-10-sulfonic acid monohydrate is dissolved by heating. Seed crystals are added to the resulting solution and allowed to stand overnight at room temperature. The precipitated crystals are collected by filtration and the collected crystals are washed with 2-propanol to afford 5.082 g of diastereomeric salts. This crude diastereomeric salt (crystal form) is suspended in 30 ml of 2-propanol and the resulting suspension is heated under reflux and left overnight at room temperature. The precipitated crystals are collected by filtration and the collected crystals are washed with 2-propanol to afford 4.227 g of crystalline diastereomeric salt.

The obtained crystals are suspended in a mixture of 43 mL methylene chloride and 43 mL water. 13 ml of 10% aqueous NaOH solution is added to the resulting suspension and stirred for 30 minutes at room temperature. The suspension is then filtered to collect insoluble crystals and the collected crystals are washed with water to collect 2.11 g of (+)-ester A as crystalline white powder. The methylene chloride layer is also washed with water and then dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 0.412 g of (+)-ester A as a white powder.

The optical purity of the obtained (+)-ester A was measured by HPLC under the same conditions as in Example 3. The optical purity of the positive isomer is above 99%.

Example 5

(+)-Ester A

Crude (±) -ester A and 7.50 g (30.0 mmol) of (S)-(+)-camphor-10 obtained in the same manner as in Reference Example 1 of 11.34 g (30.0 mmol) in 60 mL of n-propanol. Dissolve sulfonic acid monohydrate while heating. The resulting solution is stirred at room temperature for 2 hours. The precipitated crystals are collected by filtration and the collected crystals are washed with n-propanol (20 mL x 3) and dried to yield 7.966 g of crude diastereomeric salt. The crude diastereomeric salt (crystalline form) is suspended in 42 ml of n-propanol and the resulting suspension is heated to reflux and stirred at room temperature for 2 hours. The precipitated crystals are collected by filtration and the collected crystals are washed with n-propanol (12 mL x 3) and dried to yield 7.475 g of white crystalline diastereomeric salt.

The obtained crystals are suspended in a mixture of 60 ml of methylene chloride and 60 ml of water. 18 ml of 10% aqueous NaOH solution is added to the resulting suspension and stirred for 30 minutes at room temperature. The suspension is then filtered to collect insoluble crystals and the collected crystals are washed with water and dried over phosphorus pentoxide under reduced pressure to yield 4.017 g of (+)-ester A as crystalline white powder. The methylene chloride layer is also washed with water and then dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 0.600 g of (+)-ester A as a white powder.

The column in which the filler (Shinwa Kako Co., Ltd. manufactured, trade name: ULTRON ES-OVM), obtained from the obtained (+)-ester A, was composed of aminosilica resistant to denaturation and a protein (obvomucoid as a ligand). Optical purity is measured by high performance liquid chromatography (HPLC).

Column: ULTRON ES-OVM, 4.6Φ x 150mm

Mobile phase: 20 mM KH ₂ PO ₄ (pH = 4.6) / Methanol = 100/30

Flow rate: 1.0ml / min

Column temperature: room temperature

Detection: UV 247 nm.

The optically active isomer of Ester A is isolated completely under the above-mentioned conditions, and the optical purity of the (+)-isomer obtained in Example 5 is 98% or more.

Example 6

(+)-1,4-Dihydro-5-isopropyloxy-2-methyl-4- (2-trifluoromethylphenyl) 1.6-naphthyridine-3-carboxylic acid ethyl ester.

7.45 g (43.8 mmol) isopropyl iodide and 4.38 g (43.3 mmol) powdered calcium prepared in the same manner as described in 5.52 g of Example 3 in 36 mL of anhydrous DMF. Carbonate is added under nitrogen atmosphere and the mixture is stirred for 6 hours while heating at 100 ° C. To the mixture is further added 7.45 g (43.8 mmol) of isopropyl iodide and 4.38 g (43.8 mmol) of powdered calcium carbonate and the mixture is stirred under nitrogen atmosphere for 7 hours while heating at 100 ° C.

The reaction mixture is cooled to room temperature and then filtered to filter insolubles and the collected insolubles are washed with DMF. The filtrate and washings are concentrated together under reduced pressure. Thereafter, 70 ml of toluene is added to the residue and the resulting mixture is washed with two portions of 50 ml of water and 50 ml of saturated aqueous sodium chloride solution and then concentrated under reduced pressure. The residue is dissolved in 34 ml of acetone. To the resulting solution is added 1.48 g of concentrated sulfuric acid solution in 10 ml of acetone to obtain a homogeneous solution. The solution is left overnight at room temperature. The precipitated crystals are collected by filtration and the collected crystals are washed with acetone and dried to yield 6.62 g of crude sulfate of the target compound as a white crystalline product.

To 6.62 g of crude sulfate are added 80 ml of water and 50 ml of ethyl acetate, and the resulting solution is further added with concentrated aqueous ammonia to adjust its pH value to 10. The ethyl acetate layer is separated from the solution and the aqueous layer is extracted with 50 ml ethyl acetate. The organic layer is washed together with water and saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent is then removed from the solution under reduced pressure and the residue is completely dried. 5.34 g of this dried residue is dissolved in 21.3 ml of 60% ethanol while heating and gradually cooled with stirring the resulting solution. Seed gallbladder is added to the solution to precipitate the crystalline product before the solution becomes cloudy. The solution is further stirred for 1 hour before the temperature of the solution reaches room temperature. Thereafter, 5.34 ml of water is added dropwise to the mixture over 30 minutes, and the mixture is further stirred at room temperature for 2 hours. The precipitated crystals are collected by filtration and the collected crystals are washed with 40% ethanol and dried at 60 ° C. under reduced pressure for 4.77 g of the desired compound as a crystalline white powder.

Melting Point: 132.5 ~ 133.5 ℃

[α] _D ²³ : + 114 ° (c 0.518, methylene chloride).

The obtained compound was optically purified by high performance liquid chromatography (HPLC) using a column using silica gel filler (manufactured by Daicel Ltd., trade name: CHIRALCEL OF) coated with a tris (4-chlorophenylcarbamate) derivative of cellulose. Measure

Column: CHIRALCEL OF, 4.6 x 250mm

Mobile phase: Hexane / 2-propanol (195/5)

Flow rate: 0.5 ml / min

Column temperature: room temperature

Detection: UV 254 nm.

The optically active isomer was completely isolated under the above conditions, and the optical purity of the (+) -isomer obtained in Example 1 is 99% or less.

Claims (2)

(a) reacting (+)-1 optically active camphorsulfonic acid or derivatives thereof with a mixture of optically active 1, 6-naphthyridine derivatives of formula (I): (b) separating the two diastereomeric salts prepared in step (a) using the difference in solubility of the salts in the solvent; (c) (+) of the 1, 6-naphthyridine derivative, comprising the step of isolating the (+)-optically active isomer of the 1, 6-naphthyridine derivative from the diastereomer precipitated in step (b) Preparation of optically active isomers. [Formula 1] [In the above formula, each of R ¹ and R ² is independently a hydrogen atom or a C _1-4 alkyl group, and * denotes an asymmetric carbon atom.] (+) -Optical activity of the 1,6-naphthyridine derivative of the following formula (III) consisting of reacting the C _1-4 alkylating agent with the optically active isomer of the 1,6-naphthyridine derivative of the formula (I) Method for producing isomers. [Formula 2] [Wherein, each of R ¹ and R ² is independently a C _1-4 alkyl group, and the * symbol represents an asymmetric carbon atom.] [Wherein, each of R ¹ , R ² and R ³ is independently a C _1-4 alkyl group, and the * symbol represents an asymmetric carbon atom.]