JPS5936620B2 - Method for producing 5-(α-haloalkanoyl)carbostyryl derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to a method for producing novel 5-(α-haloalkanoyl)carbostyryl derivatives.

Structure of the Invention The 5-(α-haloalkanoyl)carbostyryl derivative obtained in the present invention has the general formula [wherein R represents a hydrogen atom,
R3 represents a hydrogen atom or a lower alkyl group having 1 to 2 carbon atoms, and R2 represents a lower alkyl group or an aralkyl group having 1 to 2 carbon atoms.

Moreover, x represents a halogen atom. ] This is a compound represented by The above compound of the present invention is a new compound, and β-
It is useful as an adrenergic agonist and as an intermediate in the synthesis of β-adrenergic stimulants. Details of the production of the above-mentioned β-adrenergic stimulant active ingredient compound from the compound obtained according to the present invention are as described below. The carbostyryl derivative according to the present invention is a carbostyryl derivative represented by the general formula [wherein R1 and R2 are the same as above] and the general formula [wherein R and X are the same as above, and X represents a halogen atom] .

It can be obtained by reacting with an α-haloalkanoic acid halide represented by the following formula.

In the above, examples of the lower alkyl group having 1 to 2 carbon atoms represented by R2 and R3 include methyl and ethyl groups.

Examples of the aralkyl group represented by R2 include benzyl and phenethyl groups. Furthermore, X. Examples of the halogen atom represented by χ include chlorine, bromine, and iodine atoms. In the present invention, the 5-(α
The reaction for obtaining monohaloalkanoyl) carbostyril derivatives is generally called the Friedel-Crafts reaction, and is carried out in the presence of a Lewis acid.

The Lewis acid used at this time is not particularly limited, but representative examples include anhydrous aluminum chloride,
Examples include titanium chloride. The amount of the Lewis acid to be used may be selected as appropriate, but it is usually used in an amount of 1 to 5 times the mole (preferably 2 to 4 times) of the carbostyril derivative represented by the general formula (1). In addition, carbostyril derivatives represented by general formula (1) and α represented by general formula ()
The ratio of the haloalkanoic acid halide to the haloalkanoic acid halide may be selected as appropriate, but usually the latter may be used in an equal molar to large excess (preferably 1.5 to 5 molar) of the former. This reaction may be carried out without a solvent or in a solvent.

The solvent used at this time is not particularly limited as long as it does not participate in the reaction, but carbon disulfide, nitrobenzene, methylene chloride, ethylene chloride, etc. are usually advantageously used. The reaction temperature is not particularly limited, but generally a range from room temperature to 120°C (preferably 50 to 80°C) is employed. This reaction yields the 5-(α-haloalkanoyl)carbostyryl derivative of the present invention in which the 5-position of the carbostyryl derivative represented by general formula (1) is substituted with an α-haloalkanoyl group.

The thus obtained compound of the present invention can be converted into a β-adrenergic stimulant active ingredient compound (compounds represented by general formulas () and ()) according to the method shown in the reaction scheme below.

Reaction Scheme> [In the formula, R1 to R' and X are the same as above.

R4 represents an alkyl group having 1 to 4 carbon atoms. ] Details of the method shown in the above reaction scheme are shown in Reference Examples 1 to 7 below.

EXAMPLES Examples and reference examples are provided to specifically illustrate the present invention.

Example 1 8-Methoxycarbostyryl 10y) Nitrobenzene 1
5ml and α-promobutyryl bromide 30y are mixed, and anhydrous aluminum chloride 32y is gradually added under ice cooling, followed by stirring at 55 to 60°C for 4 hours.

The reaction solution was poured into 200ml of ice water, and the precipitate formed was
Then, after washing with ethanol, recrystallization from methanol yields 5-(α-promobutyryl)-8 with a melting point of 169-170°C.
-Methoxycarbostyril 11.5y is obtained. Example
2 8-Methoxycarbostyryl 7V) After mixing 9y of chloroacetyl chloride and 10ml of nitrobenzene and gradually adding 21y of anhydrous aluminum chloride under ice cooling, 60~
Stir at 65°C for 4 hours.

The reaction solution was poured into 5007n1 of ice water, the precipitate formed was collected, washed with ethanol, and then recrystallized from tagnol to obtain 8.5y of 5-chloroacetyl-8-methoxycarbostyryl having a melting point of 243-244°C. Example 3 8-benzyloxycarbostyryl and chloroacetyl chloride were reacted in the same manner as in the above example, and the melting point was 27.
Obtain 8-benzyloxy-5-chloroacetylcarbostyryl at 5-277°C.

Reference Example 1 5-chloroacetyl-8-methoxycarpostyryl 3V obtained in Example 2 was dissolved in isopropanol 40TI12, and while heating and stirring at 60°C, isopropylamine 107 was added dropwise, followed by heating and stirring for 2.5 hours, Distill the solvent to 1/
After concentrating to 2 volumes, the precipitate was collected by saturation with dry hydrochloric acid gas and recrystallized from ethanol to obtain 1.87 g of 5-isopropylaminoacetyl-8-methoxycarbostyryl hydrochloride in the form of colorless needles.

Reference Example 2 1.0 t of 5-isopropylaminoacetyl-8-methoxycarbostyryl is dissolved in 50 ml of methanol, and while stirring under ice cooling, 0.6 t of sodium borohydride is added little by little.

After the addition was completed, stirring was continued for 1 hour, and then the reaction solution was adjusted to pH 2 to 3 with concentrated hydrochloric acid, and the precipitate was removed. The residue obtained by concentrating this solution to dryness was recrystallized from acetone and then recrystallized from ethanol to produce colorless and amorphous 5-(1-hydroxy-2-isopropylamino)ethyl 0.87 of -8-methoxycarbostyryl hydrochloride monohydrate is obtained. Reference Example 3 From 8-benzyloxy-5-chloroacetylcarbostyryl obtained in Example 3 in the same manner as Reference Examples 1 and 2,
8-Benzyloxy-5-(1-hydroxy-2-isopropylamino)ethylcarbostyryl is obtained.

Mp234-236°C Reference Example 4 30 ml of 47% hydrochloric acid was added to 2r of 5-isopropylaminoacetyl-8-methoxycarbostyryl and heated under reflux for 8 hours.

Concentrate to dryness three times while adding water. The residue was dissolved in 60 mj of water, and then an aqueous sodium carbonate solution was added to adjust the pH to 7.
The precipitated crystals are separated from P, converted into hydrochloride with hydrochloric acid, and then recrystallized from ethanol to obtain 8-hydroxy-5-isopropylaminoacetylcarbostyryl hydrochloride hydrate having a melting point of 288° C. (decomposition point) at 1.07. Reference Example 5 The compound obtained in Reference Example 4 above is subjected to the same operation as in Reference Example 2 to obtain 5-(1-hydroxy-2-isopropylamino)ethyl-8-hydroxycarbostyryl hydrochloride.

Mp2lO~212lC Reference Example 6 5-(α-promobutyryl)-8-methoxycarbostyryl obtained in Example 1 was subjected to the operations of Reference Example 1, Reference Example 4, and Reference Example 2 to obtain 5-( 1-hydroxy-
2-isopropylamino)butyl-8-hydroxycarbostyryl hydrochloride is obtained.

Mpl89-190°C Reference Example 7 In the same manner as in Reference Example 6 above, 5-(1-hydroxy-2-isopropylamino)ethyl-8-hydroxycarbostyryl hydrochloride is obtained from the compound obtained in Example 3.

Mp21O~212°C Next, the results of a pharmacological test performed on the compound obtained in the above reference example are shown.

Extracted guinea pig bronchus test The trachea was removed from a male Hartley guinea pig (body weight: 450 to 6,007 cm), and the method of Constantin [J. W. C.O.
nstantine,,J. Pharm. Pharma
cOl. 17, 384 (1965)].

The specimen was heated to 37±2°C in a lock solution (154 mmol of common salt, 5.6 mmol of potassium chloride, 2.2 mmol of calcium chloride, 2.4 mmol of sodium bicarbonate, 5 mmol of dextrose) with 95% carbon dioxide and 5% oxygen gas aerated. .6
The specimen was suspended in a 15 ml tissue bath with a load of 2 V applied. The lower end of the specimen was fixed, and the upper end was connected to a pressure transducer (Sanei Saigi, model 45072), and its tension (relaxation) was recorded isometrically. First, in order to block α-receptors in the specimen, phentolamine was added to the tissue fluid in advance to a concentration of 3 x 1067/ml.
Acetylcholine was then added to a concentration of 1 x 10-57/111 to shrink the specimen.

Continuing, Van Rossum's method [J. M. anROssu
m. , Arch. Int. PharmacOdyn. T
her. , 143, 299 (1963)], the test drug was cumulatively administered into the interstitial fluid at lower concentrations.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 represents a hydrogen atom, and R_2 has 1 to 2 carbon atoms]
represents a lower alkyl group or an aralkyl group. ] Carbostyryl derivatives represented by the general formula ▲ mathematical formula,
Chemical formulas, tables, etc. are available▼ [In the formula, R_3 represents a hydrogen atom or a lower alkyl group having 1 to 2 carbon atoms, and X and X' are the same or different and represent a halogen atom. [In the formula, R_1, R_2, R_3 and X have the same meanings as above. ] A method for producing a 5-(α-haloalkanoyl)carbostyryl derivative.