JPS597704B2 - Calbostyril Yudou Tainoseizohou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing carbostyryl derivatives.

The carbostyryl derivative obtained in the present invention has the general formula CH-CH-NH-R4 □.

R.

oR1 [In the formula, R1, R2 and R3 represent a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms.

R4 is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a cycloalkyl group, a group represented by the general formula 1 (wherein n represents an integer of 1 to 4), or 1.
Indicates a 1-dimethylphenethyl group.

The bonds shown by dotted lines at the 3rd and 4th positions to the east indicate single bonds or double bonds. However, when R4 represents a 1.1-dimethylphenethyl group, Rl. Both R2 and R3 represent hydrogen atoms, and the bonds shown by dotted lines at the 3rd and 4th positions represent double bonds. ] is a compound represented by

The present invention further includes acid addition salts of the above compounds. The above compounds of the present invention are novel compounds and are useful as β-adrenergic agonists. The carbostyril derivative according to the present invention has the following general formula: [In the formula, R1. R2,
The bonds shown by dotted lines at R3 and the 3rd and 4th positions have the same meanings as above.

] Compounds and general formula [In the formula, R4 represents the same meaning as above.

) with an amine under reductive amination conditions. General formula (I) which is the starting material of the present invention
The compound represented by is a new compound.

The compound can undergo the following reactions, for example. [
In the formula, Rl, R2, R3 and the bonds shown by dotted lines at the 3rd and 4th positions have the same meanings as above, and X represents a halogen atom.

] That is, a compound represented by the known general formula () and a compound represented by the general formula (
) is reacted with an acid halide represented by formula (V) in the presence of a Friedel-Crafts catalyst to obtain a compound represented by general formula (V).

The Friedel-Crafts catalyst used in this case is not particularly limited, but ice-free aluminum chloride, titanium chloride, etc. are generally advantageously used. In addition, the ratio of the compound represented by the general formula () and the acid halide represented by the general formula () may be selected as appropriate, but in general, the latter is used in a molar range of 1 to 5 times the former (preferably 3 to 5 times the molar equivalent). times mole)
Good to use. The above reaction may be carried out without solvent,
The reaction may also be carried out in a solvent such as an alkyl halide such as dichloroethane or dichloromethane, carbon disulfide, or nitrobenzene. Although the reaction temperature and reaction time may be selected as appropriate, the reaction proceeds advantageously by usually reacting at room temperature to 120°C (preferably 50 to 80°C) for 1 to 15 hours (preferably 3 to 10 hours). Then, by oxidizing the compound represented by the general formula () obtained by this reaction, the compound represented by the general formula (I) used as the starting material of the present invention can be obtained. This oxidation reaction can be carried out under a wide range of oxidation reaction conditions, but is usually carried out using an oxidizing agent such as selenium dioxide. The above reaction is generally carried out in a solvent, and the solvent used at this time is
Examples include ethers such as dioxane, tetrahydrofuran and diethyl ether, acetic acids such as acetic acid and ethyl acetate, and water. The reaction temperature may be appropriately selected depending on the type of oxidizing agent, etc., but it generally proceeds advantageously at room temperature or around the reflux temperature of the solvent (preferably 60°C or around the reflux temperature of the solvent). The amine represented by the general formula (), which is the other starting material of the present invention, is a known compound, and specific examples include methylamine, ethylamine, propylamine,
Alkylamines such as isopropylamine, n-butylamine, Sec-butylamine, and tert-butylamine; cycloalkylamines such as cyclohexylamine and cyclopentylamine; aralkylamines such as benzylamine, phenethylamine, and dimethylphenethylamine;
can be mentioned.

In the present invention, the reaction between the compound represented by the general formula (1) and the amine represented by the general formula () can be carried out under a wide range of reductive amination conditions.

This is usually carried out by a catalytic reduction method in the presence of a catalyst. Catalysts used at this time include, for example, platinum oxide, platinum black,
Examples include palladium black, palladium carbon, and Raney nickel. The reductive amination reaction can also be carried out in the presence of a hydrogenating agent, and examples of the hydrogenating agent used in this case include sodium boron hydride and lithium aluminum hydride. In addition, when a compound represented by general formula (1) having an unsaturated bond (double bond) at the 3rd and 4th positions is used as a raw material, the 3rd and 4th positions of the target compound to be obtained may be further reduced. It is preferable to use a hydrogenating agent with relatively mild reduction without any Although there are no particular limitations on the selection, it is usually preferable to use the latter in an amount of about 2 to 3 times the amount of the former.

This reaction is carried out in a solvent.

As the solvent used at this time, solvents used in ordinary reductive amination reactions can be effectively used, such as lower alcohols such as methanol and ethanol, dioxane,
Examples include ethers such as tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene, acetic acid, and water. Although the reaction temperature is not particularly limited, the reaction generally proceeds advantageously at room temperature to about 50°C, and is appropriately selected within this temperature range depending on the raw materials, the type of reduction method, etc. Although the reaction mechanism in this reaction is not necessarily clear, first of all, the general formula of the intermediate is represent.

It is thought that a compound represented by the following formula is produced, and the ketone group and imino group of the side chain at the 5-position are simultaneously reduced to produce the carbostyryl derivative of the present invention. The carbostyril derivative of the present invention can be prepared using hydrochloric acid, bromine, sulfuric acid,
Physiologically acceptable acid addition salts can be prepared by adding inorganic or organic acids such as maleic acid.

Examples will be given to specifically explain the present invention.

Example 1 232 t of (8-hydroxycarbostyryl-5-yl)glyoxal is dissolved in 50 ml of ethanol, 1.2 t of isopropylamine is added, and the mixture is stirred at room temperature for 30 minutes.

Furthermore, gradually add 0.67 sodium boron hydride,
Stir for 1 hour. Concentrated hydrochloric acid is added to make PHL, the resulting precipitate is removed, and the solution is concentrated to dryness. The residue was dissolved in methanol to remove insoluble matter, and concentrated to dryness. The residue was recrystallized from methanol-ethyl ether to a melting point of 21
2.17 of 5-(1-hydroxy-2-isopropylamino)ethyl-8-hydroxycarbostyryl hydrochloride is obtained in the form of colorless needles of 0-212 DEG C. (decomposition). Typical target compounds of the present invention obtained according to the above examples are illustrated below.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1, R_2 and R_3 represent a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms. Further, the bonds shown by dotted lines at the 3rd and 4th positions indicate single bonds or double bonds. ] Compounds represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (in the formula, n represents an integer of 1 to 4) or a 1,1-dimethylphenethyl group. ] There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ that are characterized by reacting with amines represented by Each bond indicated by a dotted line has the same meaning as above. However, when R_4 represents a 1,1-dimethylphenethyl group, R_1, R_2, and R_3 all represent hydrogen atoms, and the bonds shown by dotted lines at the 3rd and 4th positions represent double bonds. ] A method for producing a carbostyryl derivative represented by