JPS595568B2 - Method for producing 4-benzoyl-1-indanones - Google Patents

Description

Detailed Description of the Invention The present invention relates to a compound represented by the formula or a reactive derivative thereof in a carboxyl group, and a compound represented by the general formula [wherein R may have a lower alkyl group or a halogen atom as a substituent] The present invention relates to a method for producing a compound represented by the general formula [the symbols in the formula have the same meanings as above], which is characterized by reacting the compound represented by the following formula [representing a phenyl group].

Examples of the reactive derivative of the carboxyl group of the compound of formula (1) include acid halides and acid anhydrides.

Acid halides include acid chloride, acid bromide, acid iodide,
Examples of acid anhydrides include anhydrides of carboxylic acids of formula (1), carboxylic acids of formula (1) and other acids (e.g., organic carboxylic acids such as formic acid and acetic acid, silicic acids) Examples include acid anhydrides with inorganic acids such as boric acid and boric acid. When the phenyl group represented by R has a substituent, the substituent may be a linear or branched lower alkyl group having about 1 to 4 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl , Sec-butyl, t-butyl group), and halogen atoms (eg, fluorine, chlorine, bromine, and iodine).

One or more of these substituents, the same or different, may be substituted at any position of the phenyl group represented by R. The method of the present invention consists of reacting a compound of formula (1) with a compound of general formula ().

In addition, when compound (1) is a free carboxylic acid, it may be converted into a reactive derivative thereof and then subjected to the reaction, and when it is a reactive derivative, it may be converted to a free carboxylic acid and then subjected to the reaction. You may. The reaction is generally advantageously carried out in the presence of a catalyst, and as a catalyst, any Friedel-Crafts catalyst that can be used as a catalyst in a Friedel-Crafts reaction can be used, such as a metal halide (e.g. , aluminum chloride, aluminum bromide, aluminum fluoride, iron chloride, iron bromide, antimony chloride, antimony bromide, titanium chloride, tin chloride, tin bromide, zinc chloride, zinc bromide, bismuth chloride) or boron fluoride, etc. Lewis acids; mineral acids such as sulfuric acid, phosphoric acid, and polyphosphoric acid; and hydrogen fluoride. In addition, the reaction is advantageously carried out in the presence of a solvent, and as a solvent, the general formula ()
An aromatic compound represented by may be used, and any compound that is inert to the reaction may be used. Examples of solvents inert to the reaction include carbon disulfide, nitrobenzene, halogenated hydrocarbons (e.g., methylene chloride,
Examples include ethylene chloride, 1, 1, 2, 2 tetrachloroethane), etc. When using sulfuric acid, phosphoric acid, polyphosphoric acid, hydrogen fluoride, etc. as a catalyst, a large excess amount may be used as a solvent.

When using a Friedel-Crafts catalyst, usually 1 mole of the carboxylic acid of formula (1) or its reactive derivative is used.
~6 mol is sufficient, and there are no particular limitations on reaction conditions such as temperature and time, but the practical reaction temperature is usually -15°C to around the boiling point of the solvent used, and the reaction temperature is appropriately cooled within the same temperature range. Alternatively, it may be heated. The reaction time varies depending on the raw material compound, the catalyst, and the type of solvent used, but is usually about 1 to 5 hours. The compound of general formula () thus obtained can be separated and purified by methods known per se, such as distillation, recrystallization, and column chromatography. The compound of the general formula () thus obtained can be converted into a compound () having strong anti-inflammatory, analgesic and antipyretic effects by the following operations.

When the compound of general formula () itself is used as an anti-inflammatory, analgesic, or antipyretic agent, the usual dosage for adults is approximately 10 to 1000 η per day in the form of tablets, capsules, powders, etc. Or, a single adult dose of about 5 to
500η can be administered parenterally as an injection, suppository, etc. Example 14-carboxyindane-1
-one 17.67 and phosphorus pentachloride 22.97 are added to 100 ml of dry benzene, stirred for 1.5 hours, and then aluminum chloride 407 is added.

After stirring for 5 hours, the mixture was decomposed by adding dilute hydrochloric acid and extracted with ether.

After drying the organic layer, the solvent is distilled off under reduced pressure and the resulting crystals are recrystallized from cyclohexane to obtain 4-benzoylindan-1-one. Melting point 87-89℃ o Elemental analysis value Cl6Hl2O2 Calculated value C: 81.34, H: 5.12 Experimental value C: 81.26, H: 5.03 Example 2 4-carboxyindan-1-one 17.67 and phosphorus pentachloride 22.9 (i!) are added to 100 TI11 of dry toluene, stirred at room temperature for 1.5 hours, and then 40 y of aluminum chloride is added.

After stirring overnight, add 400 ml of 3N hydrochloric acid and decompose. After extraction with benzene, the organic layer is washed with water, an aqueous sodium hydroxide solution, and water in this order, and dried over anhydrous magnesium sulfate. The crystals obtained by distilling off the solvent under reduced pressure were separated and purified using silica gel column chromatography (silica gel 2007, eluted with chloroform), and recrystallized from acetone.
-Toluoylindan-1-one is obtained. melting point 10
5-108°C elemental analysis value Cl7Hl4O2 Calculated value C: 81.58, H: 5.64 Experimental value C: 81.59, H: 5.56 Example 3 In the same manner as Example 2, 8.87 4-(2
-4,6-trimethylbenzoyl)indan-1-one is obtained.

Melting point 159.5161.51c (recrystallization solvent benzene-
Hexane (1:1)) Elemental analysis value Cl9H,8O2 Calculated value C:8}. 98, H: 6.52 Experimental value C: 81.95, H: 6.74 Example 4 17.67 4-carboxyindan-1-one and 23 V of phosphorus pentachloride were added to 200 ml of chlorobenzene and heated at room temperature for 3 hours. After stirring, aluminum chloride 407 is added and stirred at about 65°C for 3 hours.

After cooling, decompose with water and hydrochloric acid and extract with chloroform. The extracted layer is washed with water, saturated sodium hydrogen carbonate solution, and water, and dried. The residue obtained by distilling off the solvent under reduced pressure is purified by silica gel column chromatography (silica gel 200t1 eluted with chloroform). Benzene-hexane (
144.5-1 when recrystallized from a mixed solvent of 20:5)
4-(p-chlorobenzoyl)indan-1-one is obtained as crystals with a melting point of 46°C. Elemental analysis value
Cl6HllO2Cl Calculated value C: 70.98, H: 4.101 C1: 13.
10 Experimental values C: 70.72, H: 4.01, Cl: 13.
28 Example 5 In the same manner as in Example 4, from 17.67 4-carboxyindan-1-one, 200 ml orthochlorotoluene, 237 phosphorus pentachloride, 407 aluminum chloride,
4-(p-chloro-m-methylbenzoyl)indan-1-one is obtained.

Melting point: 88-90°C (benzene-cyclohexane (3:2)
Recrystallization from a mixed solvent of 0)) Elemental analysis value Cl7Hl3
O2Cl calculated value C: 71.70, H: 4.601C1:12,
45 Experimental values C: 71.97, H: 4.39, Cl: 12.
01 Example 6 In the same manner as in Example 4, 17.6 t of 4-carboxyindan-1-one, 200 ml of fluorobenzene, 2
From 37 phosphorus pentachloride, 40 t aluminum chloride, 4-
(p-fluorobenzoyl)indan-1-one is obtained.

Melting point 93-94.5℃ o Elemental analysis value Cl6HllO2
F Calculated value C: 75.58, H: 4.36 Experimental value C: 75.37, H: 4.21 Example 7 In the same manner as in Example 4, 4-carboxyindan-1-
ion 17.67, phosphorus pentachloride 237, bromobenzene 20
0ml Aluminum chloride 407 gives 4-(p-bromobenzoyl)indan-1-one.

Melting point 154-155℃ (benzenecyclohexane (1:
1) Recrystallization from mixed solvent) Elemental analysis value Cl6Hll
O2Br calculated value C: 60.97, H: 3.52, Br: 25.
36 Experimental values C: 60.81, H: 3.41, Br: 25.
61 Reference Example 1 (a) Sodium ethoxide prepared from 1.17 sodium metal was mixed with 24 ml of absolute ethanol and 48 ml of sodium ethoxide.
Dissolve in a mixture of 1 and anhydrous dimethoxyethane, 9.5y
4-benzoyl-1-interson and 9.47 N-(
The solution was added dropwise over 20 minutes to a solution of 120 ml of anhydrous dimethoxyethane in which para-toluenesulfonylmethyl)isonitrile was dissolved while stirring under ice-water cooling.

After the addition was completed, the mixture was further stirred at the same temperature for 30 minutes, and then at room temperature for 3.5 hours. Add water and extract with ether. The extracted layer is washed with water and then dried. The residue obtained by evaporating the solvent under reduced pressure is purified by column chromatography on silica gel (silica gel 1k9, eluted with benzene-ethyl acetate (50:1)). 1-Cyano-4-benzoylindane is obtained as an oil. Elemental analysis value
Cl7Hl3ON Calculated value C: 82.57, H: 5.301 N: 5.66 Experimental value C: 82.34, H: 5.21, N: 5.43 (b) Dilute solution made from 54 ml of water and 45 ml of concentrated sulfuric acid Add 37 1-cyano-4-benzoylindanes to the sulfuric acid.

Experimental Example The following test compounds derived from the target compound of the present invention by Reference Example 1 or a similar method were examined for their analgesic and anti-inflammatory effects.

(a) Test compound A: 4-benzoylindane-1-carboxylic acid B: 4-(p-methylbenzoyl)indane-1-carboxylic acid C: 4-(p-chlorobenzoyl)indane-1-carboxylic acid (b ) Experimental method (a) Carrageenin mammary tumor method (anti-inflammatory effect) Using the method of Winter et al. [Winter et al. C
．． A. , Risley,. E. A. andNuss,.
G. W. , PrOc. SOc. Exp. BlOl. Me
d. , 111, 544 (1962)].

First, the volume of the right hind paw of the animal was accurately measured to 0.01 ml, and then the sample was orally administered, and water was additionally administered to make the total volume 5 ml. One hour later, 0.05 ml of 1% carrageenan saline was subcutaneously injected into the heel to induce a mammary tumor.

The volume of the right hind paw was measured again 3 hours after the injection of force lagenin.
The breast tumor suppression rate (%) by sample administration was calculated using the following formula.
(b) Phenylquinone rice ink method?
(Phenylquin Onewritthing) (Analgesic effect) A group of 10 male mice, 3.5 weeks old and weighing 16-20 y, were used.

First, the sample was administered orally and 30 minutes later, a 0.02% phenylquinone aqueous solution (0.1me/10v body weight dissolved in ethanol at a ratio of 5%) was injected intraperitoneally. Stimulus-induced writing and stretching responses were counted for each individual animal. Experimental results

Claims (1)

[Claims] 1. A compound represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or its reactive derivative in the carboxyl group, and a compound represented by the general formula R-H [wherein R is a lower alkyl group as a substituent, A general formula ▲ which is characterized by reacting with a compound represented by [representing a phenyl group which may have a halogen atom],
There are chemical formulas, tables, etc. ▼ A method for producing the compound represented by [symbols in the formula have the same meanings as above].