JPS5810389B2 - Production method of new acetone derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a novel acetone derivative represented by the general formula or a salt thereof, which has anti-rheumatic, anti-inflammatory,
It has analgesic, antipyretic, and brain metabolism improving effects, and is useful as a medicine.

R1 in general formula CI) is hydrogen, lower alkyl (methyl,
(ethyl, propyl, isopropoxy, etc.), R2 is hydrogen, lower alkyl which may have a substituent (the substituent is lower alkoxy (methoxy, ethoxy, propoxy, impropoxy, etc.), carboxyl, di-lower alkylamino ( dimethylamino, diethylamino, diisopropylamino, etc.).

], R3 is hydrogen, carboxyl, di-lower alkylamino (dimethylamino, diethylamino, diisopropylamino, etc.), A is carbonyl, methylene, Y is oxygen, sulfur, and B is linear or branched lower alkylene. (methylene, ethylene, trimethylene, phlopylene, etc.).

According to the present invention, the compound represented by the general formula [I] is a compound represented by the general formula [In the formula, R1, R2, R3, A, B, and Y are as defined above, and (methoxycarbonyl, ethoxycarbonyl, etc.).

It can be produced by subjecting the compound represented by ] to a de-X reaction.

This de-X reaction is preferably carried out under acidic conditions such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid.

The reaction conditions such as temperature are not particularly limited, but it is generally carried out at 10 to 200°C, and if necessary, a solvent that does not interfere with the reaction, such as water, acetic acid, methanol, ethanol, dioxane, acetone, or a mixture thereof, may be used. You can also use

Among the raw material compounds represented by the general formula [■], compounds in which R2 is a hydrogen atom may exist mostly in the enol form, which is a tautomer of the general formula [■].

The compound of general formula [I] obtained as described above may be treated with an inorganic or organic base such as potassium, calcium, aluminum, ammonium, dimethylamine, triethylamine, etc., or with hydrochloric acid, sulfuric acid, hydrogen bromide, maleic acid, etc., as desired. Salts can also be formed with inorganic or organic acids such as acid, fumaric acid, tartaric acid and the like.

The raw material compound represented by the general formula (n) used in the present invention can be synthesized, for example, by the following method.

Acylation of active methylene by reacting an ester with an active methylene compound in the presence of a basic catalyst (Claisen condensation)
and then reacted with R2-halogen in the presence of a basic catalyst.

EXAMPLES The present invention will be explained in more detail with reference to Examples below.

Example 1 5H-CI)benzopyrano[2.3-b]pyridine-
33g of 7-yl-acetonitrile to 75ml of ethyl acetate
While stirring, add a solution of 3.75 g of metallic sodium dissolved in 75 ml of absolute ethanol.
Perform centrifugal stirring for a period of time.

After cooling with water, the crystals were collected by filtration, washed with ethyl acetate, and dried.
38 g of the sodium salt of 3-b]pyridin-7-yl)acetone are obtained.

Take 2.9 g of this sodium salt, dissolve it in 15 rnl of dry dimethylformamide, add 1.6 g of methyl iodide while stirring, and continue stirring at room temperature for an additional 1.5 hours.

After the reaction is completed, it is concentrated, water is added to the residue, the separated crystals are collected by filtration, and recrystallized from ethanol, resulting in a melting point of 163.
3-cyano-3-(5H-CI)benzopyrano[2,3-b]pyridin-7-yl)-2- at 5-164.5°C
2.2 g of butanone are obtained as white needles.

Dissolve this in 5 ml of concentrated sulfuric acid, add 15 ml of water at once while stirring under ice cooling, and stir and reflux for 5 hours.

After cooling on ice, neutralizing with 30% caustic soda while stirring, collecting the precipitated crystals, drying and recrystallizing from isopropyl alcohol, 3-
(5H-(1)benzopyrano[2,3-b]pyridine-
1.61 of 7-yl)-2-butanone are obtained.

Example 2 1-cyano-1-(5H-CI)benzopyrano[2.3
-b] Dissolve 4.8 g of pyridin-7-yl)-4-ethoxycarbonyl-2-butanone in 10 ml of concentrated sulfuric acid, add 30 ml of water at once while stirring under ice-cooling, and stir and reflux for 5 hours.

After cooling on ice, the pH is adjusted to approximately 3 with 30% caustic soda, and the oily substance that separates is extracted with chloroform.

Dry with anhydrous sodium sulfate and concentrate.

The remaining oil will gradually solidify.

If recrystallized from a dioxane-water (1:1) mixture, 5-(5H-(1)benzopyrano[
2.3-b]pyridin-7-yl)levulinic acid 3.4g
is obtained as white needle crystals.

Example 3 1-cyano-1-(5H-(1,)benzopyrano[2.
3-b]Pyridin-7-yl)-5-dimethylamino-
11g of 2-pentanone was mixed with 33ml of concentrated hydrochloric acid and 66ml of acetic acid.
Dissolve in a mixture of and reflux for 60 hours.

After the reaction is completed, it is concentrated under reduced pressure, and the residue is dissolved in water and made alkaline with potassium carbonate.

The oil that separates out is extracted with benzene, dried and concentrated again.

When recrystallized from a mixture of n-hexane and benzene, the melting point is 7.
1-(5H-(1)benzopyrano[2・3
-b]pyridin-7-yl)-5-dimethylamino-2
- 7.5 g of pentanone are obtained.

This is dissolved in acetone to form a salt with maleic acid, and when recrystallized from acetone, it has a melting point of 117°C.
) Benzopyrano[2,3-b]pyridin-7-yl)-
The maleate salt of 5-dimethylamino-2-pentanone is obtained as white needles.

The following compounds can be synthesized in a similar manner.

05-methoxy-3-(5H-(1)benzopyrano[2
・3-b]Pyridin-7-yl)-2-pe○5-dimethylamino-3-(5H-CI)benzopyrano[2.3-
b] Maleate salt of pyridin-7-yl)-2-pentanone, melting point 145-146°C 02-(5H-(1) Benzopyrano[2.3-b]1.
5830 O2-(5H-[1]benzopyrano[2,3-b]hyricin-7-yl)-4-methyl-3-pentao3-
(5H-(1) benzothiopyrano[2,3-b]pyridin-7-yl)-2-butanone, 03-(5-oxo-5H-[1]benzopyrano[2,3-b,]pyridine-7- yl)-2-butanone, melting point 193.5-194
°C 03-(5H-(1)benzopyrano[2,3-b]pyridin-7-yl)levulinic acid, melting point 206-208°C 01-(5H-(1)benzopyrano[2,3-b]pyridine-7 -yl) acetone, melting point 125-126°C o 1- (5n-CI) benzopyrano [2,3-b
]Pyridin-7-yl)-2-butanone, melting point 100~
101.5°C 01-(5H-CI)benzopyrano[2,3-b]pyridin-7-yl)-3-methyl-2-butanone, melting point 92-93.5°C 0l-(5-oxo-5H- [1) Benzopyrano [2.
3-b]Pyridin-7-yl)acetone, melting point 173~
174℃ 03-(2-Methyl-5H-(1) Benzopyrano[2.
3-b]Pyridin-7-yl)-2-butanone, melting point 1
34-135℃

Claims (1)

[Scope of Claims] 1 General formula [In the formula, R1 is hydrogen, lower alkyl, R2 is hydrogen, lower alkyl which may have a substituent (the substituent is lower alkoxy, carboxyl, di-lower alkylamino) ), R3 is hydrogen, carboxyl, di-lower alkylamino, A is carbonyl, methylene, Y is oxygen, sulfur, B is linear or branched lower alkylene, X is Indicates cyan, carbamoyl, and lower alkoxycarbonyl. [Each symbol in the formula has the same meaning as above. ] Process for producing the compound or its salt;