JPH04182484A - Production of optically active 1,6-naphthyridine derivative - Google Patents

Abstract

PURPOSE:To industrially obtain the title compound useful as a treating agent for myocardial ischemia, cerebral infarct, pulmonary arterial thrombosis, arteriosclerosis, etc., having antispasmodic action on blood vessel by reacting an optically active (+)-isomer of a naphthyridine derivative with an alkylating agent. CONSTITUTION:A 1,4-dihydropyridine derivative shown by formula I (R<1> and R<2> are 1-4C alkyl; * is asymmetric carbon) is reacted with an alkylating agent (e.g. alkyl chloride or sulfonic acid alkyl ester) containing an alkyl group to give the objective compound shown by formula II (R<3> is 1-4C alkyl).

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention relates to the following general formula (■): (In the formula, R1, R2 and R3 each independently represent an alkyl group having 1 to 4 carbon atoms. , * indicates an asymmetric carbon) The optical activity of the 1,6-naphthyridine derivative (
+) Regarding the integrated manufacturing method.

(Background of the invention) JP-A-61-143382 discloses the following general formula (m
): (wherein R1 is an optionally substituted aromatic or heteroaromatic ring, R2 is a straight-chain or branched alkyl group containing up to 4 carbon atoms, or a Hensyl group, R3 is a hydrogen atom, 4 a straight-chain or branched alkyl group or an alkoxycarbonyl group containing up to 4 carbon atoms; R4 is a straight-chain or branched alkyl group containing up to 4 carbon atoms;
5 is a carboxyl group or a straight chain, branched or cyclic alkoxycarbonyl group containing up to 17 carbon atoms and optionally containing oxygen, sulfur or nitrogen atoms) It has an antispasmodic effect on blood vessels and is used for diseases of the cerebral, heart, or surrounding blood vessels such as myocardial ischemia, cerebral infarction, pulmonary artery thrombosis, arterial isthmia, and other stenosis. is listed. Although the above publication describes that the compound represented by the general formula (III) takes the form of a racemate, it does not describe the action of its optically active form at all, and the production of its optically active form is not described at all. The method is also not described.

On the other hand, BJoidl, et al., Naunyn-5
chmiedeberg'5Arch, Pharmac
ol, 337, 447-453 (I988),
The effect of the compound represented by the following formula (IIa) (wherein i-Pr represents an isopropyl group) on isolated cardiac muscle cell action potential is as follows:
It has been disclosed that optically active (+) monomers are stronger than optically active (−) monomers, and D. J. Dooley,
et al,,J,Neurochem,,49,9
00-904 (I987) states that the effect of the compound represented by formula (IIa) on [3H] PN200-110 binding [receptor binding; brain] is that optically active (+) is optically active (-) It is disclosed that it is about 13 times that of a single body.

As mentioned above, it is known that the pharmacological activity of the compound represented by formula (Ila) is that the optically active (+) compound is significantly stronger than the optically active (-) compound; It is extremely difficult to optically resolve the optically active (+) monomer from the racemic form of the compound [For example, using the acidic optical resolving agent used numerically,
Even when attempting to optically resolve the racemic form of the compound represented by formula (Ila), it was almost impossible to resolve the racemic form], and there is no known industrially useful method for producing the optically active form of the compound represented by formula (Ila).

The present inventors have determined that the general formula (I): (wherein R1 and R2 each independently have a carbon number of 1 to 4
from a mixture of optically active forms of 1,6-naphthyridine derivatives represented by By reacting this optically active (+) monomer with an alkylating agent containing an alkyl group having 1 to 4 carbon atoms, a compound of the general formula (I) containing the compound represented by formula (I[a)] The present invention was completed by discovering that it is possible to produce an optically active (+) 1,6-naphthyridine derivative represented by (ff).

Note that some of the 1,6-naphthyridine derivatives represented by the above general formula (I) are described in JP-A-60-54385; Neither the optically active form of the 1,6-naphthyridine derivative nor the optical resolution method is described.

[Object of the Invention] An object of the present invention is to provide a method for efficiently producing an optically active (+) complex of an optically active 1,6-naphthyridine derivative represented by the general formula (II).

[Structure of the Invention] The present invention relates to the following general formula (I): (wherein R+ and R2 each independently have a carbon number of 1 to 4
optical activity of 1,6-naphthyridine derivatives (
+) is reacted with an alkylating agent containing an alkyl group having 1 to 4 carbon atoms to obtain the following general formula (): (where RI, R2 and R3 are each independently a group having 1 to 4 carbon atoms). The optical activity of the 1,6-naphthyridine derivative (
+) Optical activity 1, 6 characterized by producing an integral
- A method for producing a naphthyridine derivative.

[Detailed Description of the Invention] The substance used as a raw material in the production method of the present invention is an optically active (+) 1,6-naphthyridine derivative represented by the above general formula (I).

In the above general formula (I), R1 and R2 are each independently methyl, ethyl, n-propyl, i-propyl,
1 or more carbon atoms such as n-butyl, i-butyl, t-butyl, etc.
It represents four alkyl groups, particularly preferably methyl or ethyl.

The optical activity (+) of the 1,6-naphthyridine derivative represented by the general formula (I) is added to a mixture of the optically active forms of the 1,6-naphthyridine derivative represented by the general formula (I). )-camphorsulfonic acid or its derivatives, the two diastereomeric salts produced are separated using the difference in solubility in the solvent, and then the above 1,6-naphthyridine derivative is separated from the precipitated diastereomeric salts. It can be obtained by an optical resolution method that liberates optically active (+) molecules.

In the above optical resolution method, the mixture of optically active forms of the 1,6-naphthyridine derivative represented by general formula (I) is
It may be a racemate, and is a mixture of the remaining (+) monomer and (-) monomer after a part of the optically active 1,6-naphthyridine derivative is separated from the racemic product of the 1,6-naphthyridine derivative. You can.

The racemic form of the above-mentioned 1,6-naphthyridine derivative can be produced, for example, according to the method described in JP-A-60-54385.

For example, a 1,4-dihydropyridine derivative represented by the following general formula (IV) (wherein R1 and R2 have the same meanings as above) is reacted with 1,3,5-triazine in the presence of a base. It can be manufactured by

In the above optical resolution method, the optically active (+)-camphorsulfonic acid or its derivative used as the optical resolving agent includes optically active (+)-camphor-10-sulfonic acid, optically active U(+)-camphor- 8-sulfonic acids, halides (e.g. bromination,
chlorides, etc.), especially (+)-3-bromocamphor-
1O-sulfonic acid can be mentioned as a preferred example.

Although the reaction ratio of the optically active mixture of 1,6-lunaphthyridine conductors represented by the above general formula (I) and the above optical resolution agent is not particularly limited, the 1,
It is preferable to use the optical resolving agent in an amount of 1 to 2 moles per 1 mole of optically active (+) 6-naphthyridine derivative.

In the above optical resolution method, the optically active (+) of the 1,6-naphthyridine derivative represented by general formula (I) is combined with the optically active (+)-camphorsulfonic acid or its derivative as an optical resolving agent. 1. The stereomer salt is precipitated as crystals from the solution and remains dissolved in the solution.
Separate the optical activity (=) of the 6-naphthyridine derivative.

Therefore, in the above optical resolution method, the mixture of the optically active forms of the 1,6-naphthyridine derivative represented by the general formula (I) and the above optical resolution agent are used to form two diastereomeric salts that have different solubilities. The reaction is carried out in a solvent that shows: Such solvents include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, acetone, methyl ethyl ketone,
Acetonitrile, ethyl acetate, butyl acetate, dioxane, THF, etc. can be used alone, a mixture thereof, or a mixture of these solvents and water. It is particularly preferred to use ethanol or 2-propertool.

In the above optical resolution method, after the mixture of optically active forms of the 1,6-naphthyridine derivative and the optical resolution agent are reacted as described above, a solvent is added as necessary, and the mixture is cooled. The predetermined temperature is maintained until enough crystals are extracted. At that time, stirring may be performed as necessary. Also, in order to promote the precipitation of crystals, a small amount of crystals of the same salt as the diastereomeric salt to be precipitated may be added as seeds. The above 1゜6- in the precipitated diastereomeric salt
The separation conditions, such as the type and composition of the solvent, the solid content concentration, the crystal precipitation temperature and time, are selected so that the purity of the optically active (+) naphthyridine derivative is as high as possible. Those skilled in the art can easily select such conditions.

The diastereomeric salt precipitated as described above is collected by filtration, and then, if necessary, purified, for example, by partial dissolution or recrystallization in the same solvent used to produce the diastereomeric salt. Purified stereomeric salts can be obtained.

The obtained purified diastereomeric salt was treated with sodium carbonate,
It is treated with a base such as sodium hydroxide, potassium carbonate, potassium hydroxide, etc. to dissociate, and the compound 1 represented by the general formula (I) is
, an optically active (+)-educt of a 6-naphthyridine derivative can be obtained.

In the present invention, 1,6 represented by the above general formula (I)
- Optically active (+) derivatives of naphthyridine derivatives can be used in the form of their educts, optionally in the form of adducts of the solvent used for purification, such as optical resolution or recrystallization, e.g. alcohol. You can also,
Use in the form of acid addition salts of inorganic acids (e.g. hydrochloric acid, sulfuric acid, phosphoric acid) or organic acids (e.g. acetic acid, propionic acid, citric acid, tartaric acid, malic acid, oxalic acid, methanesulfonic acid). You can also do it.

As the mixture of optically active substances of the 1,6-naphthyridine derivative represented by the general formula (I) which is a raw material in the above-mentioned optical resolution method, the 1,6-naphthyridine derivative represented by the above-mentioned general formula (I) is used as a mixture of optically active substances. The racemic form of the 1,6-naphthyridine derivative may be used, but in advance, a part of the optically active (-) substance is separated and removed from the racemic form of the 1,6-naphthyridine derivative by an appropriate method, for example, the diastereomer salt method, When the above optical resolution method is carried out using a mixture of optically active (+) monomers and optically active (-) monomers with a relatively high content ratio of optically active (+) monomers as a raw material, high optical purity is obtained. An optically active (+) compound can be easily obtained.

Examples of the alkylating agent used in the present invention include alkyl halides (e.g., alkyl chlorides, alkyl brominations, alkyl iodides, etc.), alkyl sulfonate esters, alkyl sulfate esters, trialkyloxonium salts, and the like. I can do it. The alkyl group contained in the above alkylating agent includes methyl, ethyl, n-
Propyl, i-propyl, n-butyl, i-butyl, t
-C1-C4 alkyl such as butyl may be mentioned.

When using an alkyl halide as an alkylating agent, the (+) monomer of the 1,6-naphthyridine derivative represented by the general formula (I) is mixed with a hydride of a metal, preferably an alkali metal, in an appropriate solvent. It is preferable to carry out the reaction in the presence of a base such as a carbonate or an alkoxide.

The alkylation reaction in the present invention is generally carried out in a suitable solvent. Various solvents can be used as this solvent, but preferred solvents include acyclic, cyclic or aromatic solvents such as n-pentane, n-hexane, cyclohexane, Hensen, toluene and the like. Hydrocarbons; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, etc.; diethyl ether, 1,2-
Mention may be made of ethers such as dimethoxyethane and the like; polar neutral solvents such as dimethylformamide, hexamethylphosphoric triamide, dimethyl sulfoxide and the like.

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

After the reaction is completed, the optically active (+) 1,6-naphthyridine derivative represented by the general formula (n) can be obtained in high yield by purification by methods such as extraction with an appropriate solvent and recrystallization. .

When separating and obtaining the target compound from the reaction solution, adding an appropriate inorganic acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid) or organic sulfonic acid to form a salt of the target compound will facilitate the separation of the target compound from the reaction solution. becomes easier.

In particular, it is preferable to use a sulfate. This salt of the target compound can be converted into a free form of the target compound by treatment with a suitable alkali during purification.

1 represented by general formula (II) produced by the present invention
, 6-naphthyridine derivatives (10) are inorganic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid) or organic acids (e.g., acetic acid,
It can be made into pharmacologically acceptable salts such as acid addition salts of propionic acid, citric acid, tartaric acid, malic acid, oxalic acid, methanesulfonic acid).

Next, the present invention will be explained in more detail with reference to Examples.

[Reference Example 1] (+)-1,4,5,6-tetrahydro-2-methyl-
5-oxo-4-(2-trifluoromethylphenyl)
-1,6-naphthyridine-3-carboxylic acid ethyl ester [hereinafter referred to as (10)-ester A- (i) (±)-1,4,5,6-titrahydro-2-methyl-5-oxo-4- (2-trifluoromethylphenyl)-1,6-naphthyridine-3=carboxylic acid ethyl ester [hereinafter referred to as (±)-ester A 1,4-dihydro-2,6-simethyl-4-(2-trifluoromethyl 39.7 g (0.10 mol) of pyridine-3,5-dicarboxylic acid diethyl ester (200 ml of dry N,N-dimethylformamide (DMF))
ft solution was diluted with 60% sodium hydride 4 under nitrogen atmosphere.
．． 00 g (o, io mol) of dry D M F 50 m
It was added dropwise to the Il suspension under stirring over a period of 45 minutes.

Stirring was continued for an additional 15 minutes after hydrogen evolution ceased. A solution of 8.11 g (0.10 mol) of 1,3.5-triazine in 150 ml of DMF was added dropwise to this, and the reaction mixture was heated at 110° C. for 16 hours.

DMF was distilled off from the reaction mixture under reduced pressure, and 750 mL of acetone was added to the residue, followed by stirring, and insoluble matter was filtered off.

The filtrate was concentrated under reduced pressure and the tarry residue was dissolved in methanol 4
15 mff1 was heated and dissolved. The solution was cooled to room temperature, and the precipitated crystals were filtered and washed to form a single methanol adduct of (±)-ester A, assembly 23. Og was obtained as a crystal.

(ii) 10-Ester A 28.73 g (7
0.0 mmol) and (S)-(+)-camphor-1
16.25 g (70.0 mmol) of 0-sulfonic acid was heated and dissolved in 410 ml of ethanol, seed crystals were added thereto, and the mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration and washed with ethanol to obtain 18.4 g of crude diastereomeric salt. The crude crystals were heated and dissolved in 500 mJZ of ethanol and left overnight at room temperature. The precipitated crystals were collected by filtration and washed with ethanol to obtain 16.48 g of diastereomeric salt as white crystals.

The crystals were suspended in 50ml of 0% NaOH aqueous solution and vigorously stirred at room temperature for 30 minutes. Insoluble matter was collected by filtration and washed with water to obtain 9.08 g of (+)-ester A as a white crystalline powder.

[al, :+75. 9 ° (c O,5
+9. Methanol)'HNMR (DMSOdo)
δ21, 12 (3H,t, J
=7Hz)2, 29 (3H,S) 3, 5-4. 2 (2) f, m) 5, 52
(I)1. s) 5, 87 (
IH, d, J=7Hz) 7.09 (I
H, d, J=7Hz) 7, 0-7. 5 (4H,
m) 9, 12 (jH, br, 5) 10,
72 (IH,br, 5)IR(niB
r) cm-': 3700-2400. 1660. 1620°158
0, 1495. 1465. 1445°1310,
1250. 1205. 1150°1100, 1
030. 760° [Example 1] (+)-1,4-dihydro-5-isopropyloxy-
2-Methyl-4-(2-trifluoromethylphenyl)
-1,6-naphthyridine-3-carbon ethyl ester Under a nitrogen atmosphere, 5.52 g (4.6 mmol of I) of the (+)-ester A produced in Reference Example 1 and 7.45 g of isopropyl iodide (43,8 mmol) and powdered calcium carbonate (4.38 g (43°8 mmol)) in dry D
The mixture was added to MF36mn, and the mixture was heated and stirred at 100°C for 6 hours. Then further, isopropyl iodide 7.45
g (43,8 mmol) and powdered calcium carbonate4.
38 g (43.8 mmol) was added thereto, and the mixture was heated and stirred at 100° C. for 7 hours under a nitrogen atmosphere.

After cooling the reaction mixture to room temperature, insoluble matter was filtered off,
Washed with DMF. The filtrate and washings were combined and concentrated under reduced pressure. 70ml of toluene was added to the residue, washed with 50ml of water and 50ml of saturated brine, and then concentrated under reduced pressure. Dissolve the residue in 34 mk of acetone and add 1.48 g of concentrated sulfuric acid and 10 ml of acetone to this solution.
After adding the solution and making it homogeneous, it was left standing at room temperature overnight. The precipitated crystals were collected by filtration, washed with acetone, and dried to obtain 6.62 g of a sulfate salt assembly of the title compound as white crystals.

To 6.62 g of the sulfate salt assembly of this title compound, 80 m of water was added.
IL and 50 ml of ethyl acetate were added, and then concentrated aqueous ammonia was added thereto to adjust the pH to 10. The ethyl acetate layer was separated, and the aqueous layer was further extracted with 50 mL of ethyl acetate. The combined organic layers were washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to dryness, and the resulting residue (5.34 g) was dissolved in 60% ethanol 21
．． After heating and dissolving the solution in 3 mL, the solution was gradually allowed to cool while stirring. Seed crystals were added to precipitate crystals before the solution became cloudy. After the temperature of the liquid reached room temperature, stirring was continued for an additional hour. Next, 5.34 mfl of water was added dropwise to this mixture over 30 minutes, and the mixture was further stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration, washed with 40% ethanol, and incubated at 60°C for 1
After drying under reduced pressure for 2 hours, 4.77 g of the title compound was obtained as a white crystalline powder.

Melting point: 132.5-133.5°C [α]: 3: +114° (c O, 518,
Methylene chloride) The obtained title compound was applied to a column using a packing material in which silica gel was coated with a tris(4-chlorophenylcarbamate) derivative of cellulose (manufactured by Daicel Chemical Industries, Ltd., trade name: rCHIRALCEL OF).
J) and high performance liquid chromatography (HPL).
The optical purity was measured in C).

Column: CHIRALCEL OF 4.6X 25
0mm mobile phase: hexane/2-propanol (I951
5) Flow rate: 0.5 mIt/min Column temperature: Room temperature Detection: UV 254 nm The optically active substance was completely separated under the above conditions, and the optical purity of the (+) monomer obtained in Example 1 was 99% or more. there were.

(Effect of the invention) Optical activity (+) of the 1,6-naphthyridine derivative of the present invention
The integrated production method is for optically active (+)- of the 1,6-naphthyridine derivative represented by formula (II), which is useful as an active ingredient of medicine and which has conventionally been difficult to produce from its racemate. This is a method that allows the body to be easily manufactured and has remarkable effects.

Patent applicant: Nippon Chemifa Co., Ltd. Representative Patent Attorney Yasuo Yanagawa

Claims (1)

[Claims] 1. The following general formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 and R^2 each independently have a carbon number of 1
- represents 4 alkyl groups, * indicates an asymmetric carbon) Optical activity of 1,6-naphthyridine derivatives (
+)- is reacted with an alkylating agent containing an alkyl group having 1 to 4 carbon atoms to form the following general formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R ^1, R^2 and R^3 are each independently,
represents an alkyl group having 1 to 4 carbon atoms, * indicates an asymmetric carbon) Optical activity of a 1,6-naphthyridine derivative (
+)- Optical activity 1,6 characterized by producing - body
- A method for producing a naphthyridine derivative.