KR920006783B1 - Process for preparing raticide 4-hydroxy coumarin derivatives - Google Patents

Abstract

A method for preparing 4-hydroxy-3-[1,2,3,4-tetrahydro-3-(4-( 4- trifluoromethyl-benzyloxy)phenyl)-1-naphthyl coumarin of formula (I) comprises reacting a cpd. of formula (II) with trifluoro methyl benzene halide in an alcoholic solvent in the presence of an alkali salt of t-butylalcohol. The cpd. of formula (II) is new. 4-Hydroxy coumarin derivs. of formula (I) are useful as a rodenticidal anticoagulant.

Description

Method for preparing 4-hydroxycoumarin derivative, an anticoagulant killing agent

The present invention relates to 4-hydroxy-3- [1,2,3,4-tetrahydro-3- {4- (4-tripuloolomethyl-), which is an anticoagulant killing agent represented by the following structural formula (I): A novel process for producing benzyloxy) phenyl} -1-naphthyl] coumarin.

The compound of formula (I) is a known compound, for example, described in the preparation method thereof in Korean Patent Publication No. 91-404. According to this method, 4-hydroxycoumarin is thermally condensed with a compound of the general formula (A),

1-hydroxy-3- (p-halodiphenyl) tetrarin of formula (C) is then reacted with CuCN to produce the corresponding olefin and then the resulting olefin is coupled with 4-hydroxycoumarin or ,

Or reacting 1-keto-3- (p-halophenyl) -tetrarin with CuCN and then reducing the resulting cyanotetralone to the corresponding 1-hydroxy compound, the hydroxy compound being 4-hydroxy Prepared by condensation with coumarin.

However, these methods are actually very complicated in the preparation of the intermediate reactants and the final product, the operation is not only complicated, but also the production yield is low, there is a problem in commercial production.

The present inventors have conducted a long study to solve the problems of the existing production method, and as a result, invented a new production method capable of producing the compound of formula (I) as a target compound in high yield under mild conditions.

The invention is explained in detail in the following.

1-phenylacetyl halide (XI) is reacted with an alkoxybenzene in the presence of an aluminum chloride catalyst to prepare 1- (4'-alkoxy) phenyl-2-phenyl-1-ethanol. This reaction is preferably carried out in the presence of a solvent such as methylene chloride. The reaction is preferably reacted at about 10 degrees or less. The reaction time is reacted for 1-24 hours. After the reaction, the mixture is washed with water or other solvents, extracted with a solvent such as methylene chloride, dried with a drying agent such as magnesium sulfate, and then the solvent is removed and, if necessary, purified by a conventional method such as recrystallization to prepare a target compound.

The ketone derivative (v) obtained above is reduced in the presence of an alkyl halo acetate to prepare 3-hydroxy-3- (4'-alkoxy) phenyl-4-phenylbutanoic acid alkyl ester (v). As a reducing agent, ordinary reducing agents such as zinc are used. This reaction is refluxed in the presence of iodine and an aromatic hydrocarbon solvent such as benzene and toluene. The reaction is carried out for about 30 minutes to 5 hours. The alcohol derivatives obtained above were reacted with trialkylsilane, trifluuroacetic acid and borontripulolide in a solvent such as methylene chloride to reduce the hydroxy key of the 3-watch to yield 3- (4'-alkoxy ) Phenyl-4-phenylbutanophosphate alkyl ester (i) is manufactured. The reaction is carried out under reflux conditions for about 3-24 hours.

After the reaction, the mixture was extracted with methylene chloride, washed with water, dried in a conventional manner, and the solvent was removed to prepare 3- (4'-alkoxy) phenyl-4-phenylbutanoic acid alkyl ester (Ⅶ). The ester derivative (v) obtained above was hydrolyzed with an alkali such as potassium hydroxide, sodium hydroxide in methanol, ethanol or a mixed solvent of these solvents and water to give 3- (4'-alkoxy) phenyl-4-phenylbutanoic acid (VI). ). At this time, the hydrolysis conditions use the conditions of ordinary ester hydrolysis.

Butanophosphoric acid derivative (VI) obtained above is treated with phosphorus pentachloride in the presence of tin chloride to reduce 3- (4'-alkoxy) phenyl-1-tetrarone (V). At this time, the reaction temperature is sufficiently cooled and performed at 0-10 degrees. After the reaction, extraction, purification and drying are carried out by conventional methods. The tetraron derivative (V) obtained above is reduced with a reducing agent such as sodium borohydride to prepare 3- (4'-alkoxy) phenyl-1-tetraol (IV).

Reducing conditions are used in the usual conditions, after reduction to extract the usual solvent, neutralized and dried, and removing the solvent to prepare the target compound. 4-hydroxy-3- [1,2,3,4-tetrahydro-3- (4-alkoxyphenyl) -1-nap by reacting the tetraol derivative (IV) prepared above with 4-hydroxycoumarin Til] -coumarin (III) is prepared by reaction at reflux for about 1-5 hours at about 100-110 ° C. After the reaction, the desired compound is prepared by extraction, drying filtration or removing the solvent in a conventional manner. The resulting coumarin compound (III) is refluxed with a halogenated acid such as acetic acid and / or hydrochloric acid for 5-10 hours to hydrolyze the alkoxy group to yield 4-hydroxy-3- [1,2,3,4-tetrahydro-3. -(4-hydroxyphenyl) -1-naphthyl] coumarin (II) is produced Hydrolysis conditions are performed under the conditions of hydrolysis of ordinary ethers.

The above-mentioned coumarin compound (II) is reacted with trifluorofluoromethylbenzene halide to give 4-hydroxy-3- [1,2,3,4-tetrahydro-3- [4- (4-trifluorofluoromethyl Benzeneoxy) phenyl] -1-naphthyl] -coumarin (I) is prepared.

The reaction is reacted with trifluoromethylbenzene halide in an alcohol solvent in the presence of an alcohol, preferably an alkoxide of an alkali metal of t-butyl alcohol. After the reaction, extraction, drying, washing and removing the solvent in a conventional manner to prepare the target compound.

This is represented by the following scheme.

Wherein R and R 1 are lower alkyl groups having 1 to 4 carbon atoms and X represents chlorine, cancellation or iodine.

All intermediates produced in the present invention are novel materials. The temperature in the previous description and in the following examples all represent degrees Celsius. Next, the present invention will be described in more detail by way of examples.

Example 1

[Preparation of 1- (4'-methoxy) phenyl-2-phenyl-1-ethanone]

In a three-necked flask, 100 g of phenyl acetyl chloride (XI), 73.4 g of anisole, and 600 ml of methylene chloride are added and stirred. 94.9 g of aluminum chloride is carefully added in small portions below 10 ° C. and then stirred for 16 hours. Pour the reactants carefully, stirring the container with water and hydrochloric acid. The reaction is washed with water and extracted with methylene chloride. The extract was dried over magnesium sulfate, filtered and distilled under reduced pressure to remove the solvent and recrystallized to obtain 127.2 g of the product.

(Yield 87% mp 71-73)

NMR (CDCl,) δ 3.84 (S, 3H), 4.22 (S, 2H), 6.91 (d, 2H, J = 8.5 μs), 7.22-7.34 (m, 5H), 8.00 (d, 2H, J = 8.5 ㎐)

Example 2

[Preparation of 3-hydroxy-3- (4'-methoxy) phenyl-4-phenyl butanoic acid ester]

In a three-necked flask, 134 g of the ketone derivative obtained in Example 1, 42.6 g of zinc, and 370 ml of benzene were refluxed for 1 hour, 108.9 g of ethyl bromoacetate, 0.537 g of iodine, and a small amount of benzene. Add a small amount by mixing and reflux for 1 hour. After cooling to room temperature, 15% sulfuric acid was added, extracted with benzene, the organic layer was treated with 10% sodium bicarbonate, washed three times with water, dried over magnesium sulfate, and distilled under reduced pressure to remove the solvent.

(Yield 96.6%) 179.8%

NMR (CDCl,) δ 1.08 (t, 3H), 3.76 (S, 2H), 3.81 (S, 3H), 3.94-4.01 (q, 2H), 4.21 (S, 2H), 6.90 (d, 2H, J = 8.5 Hz), 7.21-7.32 (m, 5H), 7.98 (d, 2H, J = 8.5 Hz)

Example 3

[Preparation of 3- (4'-methoxy) phenyl-4-phenyl butanoic acid ester]

In a three-necked flask, 250 g of the alcohol derivative obtained in Example 2 was dissolved in 300 ml of methylene chloride, and 105.5 g of triethyl silane, 376.23 g of trifluoacetic acid, and 3 ml of borontrapulolide were added. Add. The solution is refluxed for 8 hours and then washed with 30% potassium carbonate. Extract with methylene chloride, wash twice with water, dry with magnesium sulfate, filter and remove solvent.

(Yield 91%) 223.7% of production

Example 4

[Preparation of 3- (4'-methoxy) phenyl-4-phenyl butanoic acid (VI)]

In a three-necked flask, 6.0 g (0.019 mol) of the ester derivative obtained in Example 3 was dissolved in 20 ml of ethanol, and 4.3 g (0.076 ml) of potassium hydroxide was dissolved in 15 ml of water. This solution is refluxed for 8 hours. After cooling to room temperature, the solvent is removed, water is added, extraction is performed with benzene, and the water layer is acidified with 10% hydrochloric acid (pH 1-2). Again extracted with methylene chloride, washed with water, dried over magnesium sulfate, filtered and concentrated to yield 4.62 g of product.

(Yield 85% mp 122-125)

NMR (CDCl,) δ 2.55-2.72 (q, 2H), 2.88 (d, 2H, J = 7 ′), 3.40-3.51 (q, 1H), 3.76 (S, 3H), 6.78 (d, 2H, J = 9 μs), 7.00-7.05 (m, 5H), 7.18 (d, 2H, J = 9 μs)

Example 5

[Preparation of 3- (4'-methoxy) phenyl-1-tetrarone (V)]]

Into a 50 ml three-necked flask, 6 g of butanophosphate derivative (VI) obtained in Example 4 was added and 20 ml of benzene was added. The solution is cooled sufficiently in ice bath, water, and water bath, and then added in small amounts of 9.3 g (0.045 mol) of phosphorus, and then dissolved in an ice-water bath and refluxed for 1 hour when completely dissolved. After cooling to room temperature and cooling again with an ice-water bath, 7 ml of tin chloride is dissolved in benzene and added in small portions. The solution is stirred at 0-10 ° C. for 1 hour. After adding ice / water, the mixture was extracted with a small amount of ether and IN hydrochloric acid and extracted with 10 ml of 5% KOH, sat-NaCl, water, dried over magnesium sulfate, filtered and the solvent was removed.

(85% yield, mp 102-105) is obtained.

NMR (CDCl,) δ 2.68-2.75 (m, 2H), 3.06 (d, 2H, J = 8 Hz), 3.30 (m, 1H), 3.71 (S, 3H), 6.82 (d, 2H, J = 12 I), 7.10-7.29 (m, 4H), 7.4 (d, 1H, J = 7.5 kPa), 7.98 (d, 1H, J = 7.5 kPa)

Example 6

[Preparation of 3- (4'-methoxy) phenyl-1-tetraol (IV)]

Into a 50 ml three-necked flask, 0.8 g of sodium borohydride was added in small portions while stirring and adding 20 g of tetraron derivative (V) obtained in Example 5 and 20 ml of ethanol. Stir for 4 hours, then pour the reaction into water and acidify with 10% hydrochloric acid (pH 2). Extract with methylene chloride, wash with water, wash with sodium bicarbonate, dry over magnesium sulfate and remove the solvent under reduced pressure.

4.39 g (87% yield mp 107-109) of product are obtained.

NMR (CDCl,) δ 1.93 (q, 2H), 2.45 (m, 1H), 2.9 (m, 2H), 3.8 (S, 3H), 4.97 (q, 1H), 6.87 (d, 2H, J = 9 Viii), 7.1 (d, 1H, J = 7.5 μs), 7.18-7.29 (m, 4H), 7.62 (d, 1H, J = 7.5 μs)

Example 7

[Production of 4-hydroxy-3- [1,2,3,4-tetrahydro-3- (4-methoxyphenyl) -1-naphthyl] -coumarin (III)]

Into a 100 ml three-necked flask, 12.64 g of tetraol derivative (IV) obtained in Example 6, 8.10 g of 4-hydroxycoumarin and 25 ml of acetic acid were added, heated to 105 ° C, and dissolved, and 3.4 ml of 80% sulfuric acid was added dropwise while stirring. Then reflux at 110 ° C. for 3 hours. The reaction mixture is concentrated completely by vacuum rotary evaporator, to which water is added and extracted with methylene chloride. Dry the extract with magnesium sulfate, filter and remove the solvent. Recrystallization from petroleum ether (bp30-70) gave 18.06 g (91% yield) of the product.

NMR (CDCl,) δ 2.15 (m, 2H), 2.56 (m, 1H), 2.8-3.1 (m, 2H), 3.70 (S, 3H), 5.17 (m, 1H), 6.63-798 (m, 12H )

Example 8

[Production of 4-hydroxy-3- [1,2,3,4-tetrahydro-3- (4-hydroxyphenyl) -1-naphthyl] -coumarin (II)]

In a 250 ml three-necked flask, coumarin derivative (III) obtained in 20.0 g of Example, 50 ml of acetic acid and 39 ml of 47% aqueous acid was added, and the solution was refluxed for 6 hours. After cooling to room temperature, add a small amount of methylene chloride and extract with 10% sodium hydroxide solution. The aqueous solution is acidified (pH 2) with 10% hydrochloric acid and then extracted with methylene chloride. The organic layer is dried over magnesium sulfate, filtered and the solvent is removed under reduced pressure.

Obtain 17-95% (93% yield) of the product.

NMR (CDCl,) δ 1.92 (m, 2H), 2.30 (m, 1H), 2.90-3.10 (m, 2H), 4.95 (S, 1H), 6.75-8.0 (m, 12H)

Example 9

Preparation of [4-hydroxy-3 [1,2,3,4-tetrahydro-3- [4- (4-trifluoromethyl-benzeneoxy) phenyl] -1-naphthyl] -coumarin (I) ]

30 ml of tert-butyl alcohol is added to a 500 ml three-necked flask under nitrogen gas, 1.8 g of potassium is added thereto, and the mixture is stirred until potassium is dissolved. 12.91 g of coumarin derivative (II) obtained in Example 8 was dissolved in 100 ml of butyl alcohol, and then stirred for 30 minutes. The solvent was removed by a vacuum rotary evaporator heated to 70 ° C., the solid was dissolved in 100 ml of dimethylformamide, and 8.0 g of trifluoromethyl benzene bromide was added thereto. After stirring for 16 hours, it is diluted with 100 ml of water and extracted with 100 ml of ether. Wash with water and dry with magnesium sulfate. After filtration the solvent is removed under reduced pressure.

15.1 g (83% yield, mp 86-88) are obtained.

NMR (CDCl,) δ 2.31 (t, 1H), 3.00-3.12 (m, 3H), 4.70 (t, 1H), 4.85 (q, 1H), 5.09 (d, 2H, J = 6Hz), 6.9 ( t, 2H), 7.1-7.33 (m, 8H), 7.48-7.67 (m, 6H)

Claims (5)

A process for preparing a compound of formula (I) by reacting a compound of formula (II) with trifuluromethyl benzene halide. A compound of formula (II) A process for preparing the compound of formula II by hydrolysis of the compound of formula III. R is a lower alkyl group having 1-4 carbon atoms. The compound of formula (III) R is a lower alkyl group having 1-4 carbon atoms. A method of preparing the compound of formula III by reacting the compound of formula IV with 4-hydroxycoumarin. R is a lower alkyl group having 1-4 carbon atoms.