JPS596862B2 - Method for producing 5-(1,2-epoxyalkyl)carbostyryl derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 5-(1.2-epoxyalkyl)carbostyryl derivatives.

The 5-(1.2-epoxyalkyl)carbostyryl derivative obtained by the present invention has the general formula [wherein R^1, R^
2 and R^3 are the same or different hydrogen atoms, C_1~
Indicates the lower alkyl group of C_3.

The dotted lines at the 3rd and 4th positions indicate saturated bonds or double bonds.

] This is a compound represented by The above-mentioned compound of the present invention is a new compound, and is useful as a bronchodilator, peripheral vasodilator, and cerebral vasodilator by reacting the compound with an alkylamine, for example, to form 5-[(2-alkylamino-1-hydroxy). It is important as an intermediate for the synthesis of [alkyl]carbostyryl derivatives. 5-(1・
2-Epoxyalkyl]carbostyryl derivatives can be prepared by using a known reducing agent to convert the general formula [wherein R1, R2, R3 and 3
- The dotted line at the 4th position is the same as above, and X represents a halogen atom.

] It is produced by reducing the 5-α-halogenoalkanoylcarbostyryl derivative represented by the following formula. The starting material of the present invention, that is, the compound represented by formula (1), is a new compound, and the compound can be obtained, for example, as follows.

That is, the first step involves using a known carbostyril derivative represented by the general formula [in which R1, R2, and the dotted line at the 3.4-position are the same as above] and a general formula [in which R3 is the same as above, and X' is a halogen A known acid halide represented by (atom is shown) is reacted in the presence of a known (Friedel-Crafts catalyst).

Next, in the second step, using a halogen molecule or a halogenating agent, the general formula obtained in the first step [in the formula R1, R2, R3
and the dotted lines at the 3rd and 4th positions are the same as above] is halogenated.

The first step and the second step will be explained in detail below. 1st
The compound represented by formula (), which is the starting material for the process, is a known carbostyril derivative.

The compound represented by the formula (), which is the other starting material in the first step, is also a known acid halide, and specific examples include...acetyl halide, propionyl halogenide, -n halogenide. -butyryl and the like, and examples of the mono-rogen atom include chlorine, bromine and the like. The ratio of the compound represented by formula () and the compound represented by formula () to be used is usually from equimole to 5 times the mole of the former, preferably from equimole to 3 times the mole of the latter. As the Friedel-Crafts catalyst used in the first step, known catalysts are widely used, such as anhydrous aluminum chloride, titanium chloride, and the like. The proportion of the compound represented by the formula () and the Friedel-Crafts catalyst to be used is usually from 1 to 5 times the mole of the former, preferably from 1 to 4 times the mole of the latter. The reaction in the first step may be carried out in the presence of a solvent such as an alkyl halide such as dichloroethane or dichloromethane, carbon disulfide, or nitrobenzene, or an excess acid halide may be used as the solvent.

In the first step, the reaction temperature is usually room temperature to 120°C, preferably 50 to 80°C, and the reaction time is usually 1 to 15 hours, preferably 3 to 10 hours. Next, in the second step, the halogenation reaction of the 5-alkanoylcarbostyryl derivative represented by the above formula () can be carried out using a halogen molecule or a halogenating agent such as N-halogenosuccinimide.

A compound represented by formula () and a halogen molecule or...
The ratio of the latter to the former is usually 1 to 10 times the former, preferably 1 to 5 times the former. Examples of the halogen include chlorine and bromine. The solvent used in the reaction in the second step is suitably a halogenated alkyl solvent such as dichloromethane, dichloroethane, chloroform, or carbon tetrachloride. In the second step, the reaction temperature is usually between ice cooling and the boiling point of the reaction solvent, preferably between room temperature and 40°C, and the reaction proceeds easily at this temperature. The reaction time is usually 1 to 10 hours. There is no problem in using a radical reaction initiator such as benzoyl peroxide, azobisisobutyronitrile, etc. in the second step reaction. The starting material represented by formula (1) can be obtained as described above. Known reducing agents are widely used in the present invention, such as sodium borohydride,
Examples include lithium aluminum hydride.

The ratio of the compound represented by formula () and the reducing agent to be used can be selected widely depending on the type of reducing agent, temperature, etc., but usually the former is used in an equimolar to 5-fold molar range, preferably equimolar. It is desirable to use ~3 times the mole. As the solvent in the reaction of the present invention, when using sodium borohydride as a reducing agent, a basic aqueous solution such as caustic soda,
A mixed solvent with a lower alcohol such as methanol, ethanol, isopropanol and a basic aqueous solution is suitable;
When using lithium aluminum hydride as a reducing agent, it is preferable to use a solvent such as tetrahydrofuran or diglyme.

In the present invention, the reaction temperature is usually 0 to 50°C, preferably O
It is preferable to carry out the reaction at a temperature of ~30°C.

The reaction time is usually 1 to 10 hours, preferably 3 to 8 hours. The above-mentioned 5-(1,2-epoxyalkyl)carbostyryl derivative obtained by the present invention can be prepared using a formula useful as a bronchodilator, a peripheral vasodilator, and a cerebral vasodilator according to the method shown in the reaction scheme below. 5−[(
2-alkylamino-1hydroxy)alkyl]carbostyryl derivatives. [Reaction Scheme] [In the formula, R1, R2, R3 and the dotted lines at the 3rd and 4th positions are the same as above.

R4 and R5 are the same or different and are hydrogen atoms, C1 to C4
represents a lower alkyl group. ] The ratio of the compound represented by formula (V) and the compound represented by formula () of the present invention is usually such that the latter is used in equimolar to large excess, preferably 5 to 10 times the molar amount of the former. Since the amine () itself used as a raw material in this reaction is used as a solvent, it may be used without a solvent, but preferably lower alcohols such as methanol, ethanol, isopropanol, aromatic hydrocarbons such as benzene, toluene, xylene, etc. - It is desirable to use hexane, cyclohexane, dioxane, etc. as the solvent.

The reaction temperature can be from room temperature to 110°C, but when the amine itself is used as a solvent, it is preferable to reflux at the boiling point of the amine. The reaction time is usually 1 to 20 hours, preferably 3 to 10 hours. Next, one embodiment of the first step of producing a 5-alkanoylcarbostyryl derivative represented by the formula () by reacting a known carbostyryl derivative represented by the above formula () with an acid halide represented by the formula () , halogenated 5-alkanoylcarbostyryl derivative represented by formula () to obtain 5-α- represented by formula (1)
An embodiment of producing a halogenoalkanoylcarbostyryl derivative is shown in Reference Example 1 and Reference Example 2, respectively, and further examples of the present invention are shown.

Further, production examples of 5-[(2-alkylamino-1-hydroxy)alkyl]carbostyryl derivatives represented by formula () are shown as Reference Examples 3 to 5. Reference Example 1 10 t (0.062 mol) of 8-hydroxycarbostyryl, 20 ml of carbon disulfide and 187 n-butyryl chloride (
Add aluminum chloride 25y (0.197 mol) little by little under ice-cooling and stirring, and mix thoroughly.

Next, after heating at a bath temperature of 80° C. for 10 hours, the carbon disulfide layer is removed by tilting, and crushed ice is added to crystallize the residue. The precipitated crystals were collected, washed with water, dried, and then recrystallized from methanol to give 5-n-butyryl-8- with a melting point of 225°C (decomposition point).
12.77 hydroxycarbostyril is obtained. Reference example
25-n-butyryl-8-hydroxycarbostyryl 2
Chloroform 500a is added to 3.1f (0.1 mol), and bromine 167 (0.1 mol) is gradually added dropwise while stirring at room temperature, and stirring is continued until the color of bromine disappears.

After concentrating to dryness, the residue was recrystallized from methanol to give 5(α-bromo-n-
butyryl)-8-hydroxycarbostyryl 24.67
get. Example 1 6.27 (0.02 mol) of 5-(α-promobutyryl)-8-hydroxycarbostyryl was added to 200 T of methanol.
Sodium borohydride 2.27 (0.
10% caustic soda aqueous solution 2 in which 058 mol) was dissolved
0 ml was gradually added dropwise under ice-cooling and stirring.

After stirring at room temperature for 4 hours, it was concentrated to dryness under reduced pressure, and 50% of water was added to the residue.
m1 and then hydrochloric acid to adjust the pH to 7 to 8. The precipitated crystals were collected, washed with water, dried, then dissolved in a small amount of ethanol, and crystallized by adding ether under ice cooling to obtain a solution with a melting point of 211 to 212. Colorless prism crystal 5-(1・
2.77% of 2-epoxybutyl)-8-hydroxycarbostyryl are obtained. Example 2 10 t (0.039 mol) of 5-chloroacetyl-8-methoxy-1-methylcarbostyryl was added to 250 mol of methanol.
ml of sodium borohydride under stirring under ice-cooling.
Add y (0.16 mol) little by little.

After stirring at the same temperature for 1 hour, stirring was continued at 60°C for 3 hours. After the reaction is completed, it is filtered, and the solution ▲ is concentrated to dryness under reduced pressure. The residue was dissolved in chloroform 200WLI and washed with water. The chloroform layer was dried over sodium sulfate, concentrated to dryness, and recrystallized from ether to give light brown powder crystals with a melting point of 1.83-185°C, 5-(1,2-epoxyethyl)-8-methoxy-1-methylcarboxylate. Styril 4.17 is obtained. Example 3 9.17 (0.038 mol) of 5-chloroacetyl-8-hydroxy-3,4 dihydrocarbostyryl was suspended in 250 ml of methanol, and 67 (0.16 mol) of sodium borohydride was added under stirring under ice cooling. Add little by little.

After stirring at the same temperature for 1 hour, stirring was continued at 6°C for 3 hours. After the reaction is completed, the filtered solution is concentrated to dryness under reduced pressure. The residue was dissolved in 200 ml of chloroform and washed with water. The chloroform layer was dried with sodium sulfate, concentrated to dryness, and Mp
．． l32l 5-(1,2-epoxyethyl)- at 35°C
8hydroxy-3,4-dihydrocarbostyryl 3.2
Get 7. Reference example 3 3,07 (0.013 mol) of 5-(1,2-epoxybutyl)-8-hydroxycarbostyryl was dissolved in methanol 5
0ml of isopropylamine 10W11 (0.0ml).
12 mol) and stirred at 60°C for 5 hours.

Then, concentrate to dryness under reduced pressure and add 20ml of ethanol.
After repeating concentration and drying to remove unreacted amine, 15 ml of isopropyl alcohol was added and concentrated hydrochloric acid was added under ice cooling to bring the pH to 2-3 and crystallize. The precipitated crystals were collected and recrystallized from ethanol to give a melting point of 210-212.
0.67° C. of white powdery crystals of 8-hydroxy-5-[(1-hydroxy-2-isopropylamino)butyl]carbostyril hydrochloride are obtained. Reference example 4 5-(1,2-epoxyethyl)-8-methoxy-1-
1.47 (0.006 mol) of methylcarbostyryl
Dissolved in 0ml methanol and 5ml of isopropylamine (
0.06 mol) and stirred at 60°C for 5 hours, then concentrated to dryness under reduced pressure.

Add 30 ml of acetone to the residue to dissolve it, and add concentrated hydrochloric acid under ice cooling to crystallize. Further, the product is recrystallized from ethanol to obtain 0.47 of colorless powdery crystals of 5[(1-hydroxy-2-isopropylamino)ethyl]-8-methoxy-1-methylcarbostyryl hydrochloride having a melting point of 178-180°C. Reference example 5 5-(1,2-epoxyethyl)-8-hydroxy-3
- 5-[(2-isopropylamino-1-hydroxy)ethyl]-8-hydroxy-3,4-dihydrocarbostyryl monohydrochloride is obtained in the same manner as in Reference Example 4 using 4-dihydrocarbostyryl.

Claims (1)

[Claims] 1 General formula ▲ Numerical formulas, chemical formulas, tables, etc. , X represents a halogen atom. The dotted lines at the 3rd and 4th positions indicate saturated bonds or double bonds. ] There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1, R^2, R^3 and 3 - The dotted line at the 4th position is the same as above] A method for producing a 5-(1,2-epoxyalkyl)carbostyryl derivative.