KR820000196B1 - Process for preparing fluoro acylresorcins - Google Patents

Abstract

Title compds. (I; R1 = C1-8 Perfluoroalkyl, 2,2,3,3-tetra fluorocyclobutyl; R2,R4 = H, C1-10alkyl, C2-18aliphatic acyl; R3R5 = C3-18 alkyl, halogen, NO2, p-toluenesulfonyl, cyclopentyl, benzyl, methylthio) useful as pharmaceuticals and cosmetics, were prepd. by reaction of II and III(Y = OH, amino, acyloxy, alkoxy, halogen) in the presence of Friedel - trafts catalyst. Thus, 194 g 4-n-hexyl resorcine in 31C2H5Cl was acylated with 260 g (CF2CO)2O in the presence of AlCl3 to give 264 g I(R1 = CF3; R2,R3,R4 = H; R5 = n-hexyl).

Description

[Name of invention]

Method for preparing fluoroacyl resorcin

Detailed description of the invention

The present invention relates to a process for the preparation of the novel fluoroacyl resorcin of the following general formula (I), which is useful as medicines, cosmetics and pesticides.

In the general formula, R ₁ represents a perfluoroalkyl group or 2,2,3,3-tetrafluorocyclobutyl group having 1 to 8 carbon atoms, R ₂ and R ₄ are the same or different from each other, a hydrogen atom, 1 to A linear or branched alkyl group of 10, an aliphatic acyl group of 2 to 18 carbon atoms, benzoyl, salicyloyl or phenylacetyl group, and R ₃ and R ₅ are the same or different from each other and an alkyl group of 3 to 18 carbon atoms, a halogen atom, a nitro group or p-toluenesulfonyl group, cyclopentyl, cyclohexyl, cycloheptyl, cyclododecyl, methylcyclohexyl, dimethylcyclohexyl, benzyl or methylthio group, or a group of the following general formula

Wherein F represents a —CH ₂ — or —S— group when G is a R ₅ group or a R ₃ group when G is —CH ₂ — or —S—, and R ₁ , R ₂ and R ₄ are as defined above As defined, R ₃ also represents a hydroxy, methoxy, methyl or cyano group and R ₅ also represents a methyl group.

However, 1) as defined above, except that one of the groups R ₃ and R ₅ is hydrogen,

2) as defined above except that R ₁ is a trifluoromethyl group, or

3) The other one of R ₃ and R ₅ may represent a hydrogen atom or an ethyl group as defined above except that R ₂ and R ₄ are a hydrogen atom or a methyl group.

Substituted fluoroacylsolecins of formula (I) may be prepared as follows.

The resorcin of formula (II) or a derivative thereof is prepared in the presence of a catalyst (Friedel-Crafts-catalyst) and a solvent at a temperature ranging from -80 ° C to the boiling point of the solvent, preferably at room temperature. Acylation is performed using carboxylic acids or reactive derivatives thereof.

In the general formula, R ₁ to R ₅ are as defined above, and Y represents a hydroxy or amino or acyloxy or alkoxy group or a haloken atom.

Suitable solvents are aliphatic hydrocarbons, carbon disulfides, halogenated, especially chlorinated aliphatic hydrocarbons, ethers, aromatic hydrocarbons, ie benzene, toluene, chlorobenzene, dichlorobenzene, as well as inorganic solvents, ie phosphorus pentachloride, polyphosphoric acid, phosphoric acid, Sulfuric acid;

Catalysts include Lewis acids, i.e., anhydrous aluminum chloride, ferric chloride, zinc chloride, borotrifluoride or their etherates, tin tin chloride, antimony-tri- or pentahalide, phosphorus-tri- or pentahalide , Phosphorus pentoxides or inorganic acids, ie hydrochloric acid, hydrobolic acid, sulfuric acid, polyphosphoric acid or chlorosulfonic acid or organic acids, ie P-topluenesulfonic acid are suitable.

Compounds of the general formula (I) in which R ₂ and / R ₄ obtained according to the above process are hydrogen atoms, if necessary, for example, are etherified with alkyl halides or esterified with, for example, acid halides or acid anhydrides. R ₂ and / or R ₄ can be converted into the compound of general formula (I) as described above.

Starting compounds of formula (II) are generally known in the literature and can be prepared according to processes known in the literature.

For example, the known compound of the following general formula (IV) is acylated with the compound of the following general formula (V).

Wherein Y is as defined above and R ₅ ′ represents an optionally substituted alkyl group as defined for R ₅ except for the —CH ₂ — group.

The resulting acyl compound is subsequently treated with hydrogen to catalytically reduce to yield the corresponding compound of formula (II) alkylated at the 5-position.

Alternatively, starting compounds of formula (II) in which R 5 represents a halogen atom can be obtained by halogenating the compound of formula (VI).

Compounds of formulas (II) and (IV) (when R ₅ is an alkyl group) are known compounds of the general formula (IV) wherein R ₃ '-Mg Hal (wherein R ₃ ' is -CH _2- To an alkyl group as defined for R ₃ except for the group.).

In the general formula, R ₅ is as described above, and R ₈ represents an alkyl group. Subsequently, the corresponding compound having an aliphatic acyl group at the 3-position is liberated by hydrolysis, the R ₈ group is optionally removed using anhydrous aluminum chloride, and the aliphatic acyl group is reduced to an R ₃ group having an alkyl group. If R ₂ and R ₄ are intended as compounds of the general formula (II), then the corresponding substituted 4-methyl-7-hydroxy-coumarin of the general formula (VII) is represented by the general formula R ₃ '-COX Esterified with a carboxylic acid or a derivative thereof, wherein R ₃ ′ and X are as described above, to obtain a compound of the following general formula (IV), followed by the use of anhydrous aluminum chloride Formed by conversion to a compound and then heating with sodium hydroxide solution followed by hydrolysis with sulfuric acid to catalytically reduce the ketone of formula (X) with amalgamated zinc and hydrochloric acid to give the desired compound of formula (II). [Reference: Organic Synthesis Coll, Vol, 3,281ff].

If desired, the obtained compound can be converted, for example, by etherification or esterification to the corresponding compound of formula (II) except that R ₂ and R ₄ are hydrogen atoms.

Formula (I) compounds are useful as pharmacological and / or pesticides. In particular, the compound is effective against bacteria, phytodermal pathogens, yeasts, fungi, and phytopathogenic fungi, and because the compound exhibits inhibitory effects on various major enzymes and cell cultures of carbohydrate metabolism, Delay mitosis. Therefore, these compounds are suitable for the treatment of acne, dandruff, bacterial skin infections, filamentous fungi, psoriasis, young skin, and hyperkeratosis of the skin, and are useful as plant herbicides such as wild oats as well as diseases that rot due to moisture in plant cultivation. Do. Several compounds of formula (I) also exhibit antiparasitic activity.

The following known substances and novel compounds were used to compare the inhibitory effects on bacteria and fungi, cell culture and enzymatic activity.

[Base compound]

2,4-dihydroxy-trifluoroacetophenone = A

5-ethyl-2,4-dihydroxy-trifluoroacetophenone = B

3-ethyl-2,4-dihydroxy-trifluoroacetophenone = C

[New compound]

2,4-dihydroxy-5-n-hexyl-trifluoroacetophenone = E

2,4-dihydroxy-3-iso-butyl-trifluoroacetophenone = F

2,4-dihydroxy-5-iso-pentyl-trifluoroacetophenone = G

2,4-dihydroxy-3- (4'-methyl) -cyclohexyl-trifluoroacetophenone = H

2,4-dihydroxy-5- (3 ', 5'-dimethyl) -cyclohexyl-trifluoro acetophenone = I

2,4-dihydroxy-5-n-nonyl-trifluoroacetophenone = J

2,4-dihydroxy-3-iso-hexyl-trifluoroacetophenone = K

2,4-dihydroxy-3-cyclododecyl-trifluoro acetophenone = L

2,4-dihydroxyoxy-3-isodecyl-trifluoro acetophenone = M

2,4-dihydroxy-3-cyclopentyl-trifluoroacetophenone = N

2,4-dihydroxy-3-cycloheptyl-trifluoro acetophenone = O

2,4-dihydroxy-3-isopropyl-trifluoroacetophenone = P

2,4-dihydroxy-3-methyl-trifluoroacetophenone = Q

2,4-dihydroxy-5-chloro-trifluoro acetophenone = R

2,4-dihydroxy-3-methyl-pentafluorothiophenone = S

2,4-dihydroxy-5-n-decyl-trifluoro acetophenone = T

2,4-dihydroxy-3-n-pentyl-trifluoroacetophenone = U

2,4-dihydroxy-3-n-propyl-trifluoroacetophenone = V

Inhibitory effects on bacteria and fungi were tested by serial dilution test and Agar diffusion test (hole-test).

Bacteria used: Staphylococcus aureus SG 511, Streptococcus Aronson, Streptococcus pyogenes AT CC 86 68,

Fungi used: Candida albicans AT CC 10231, Trichophyton mentagrophytes AT CC 9129 and Aspergillus niger

[Continuous Dilution Test]

Nutritional Medium

Pomegranate extract: Staphylococcus aureus SG 511

Composition: peptone 10g sodium chloride 3g

Meat Extract 8g 2g Sodium Diphosphate (Na ₂ HPO ₄ ) 2g

1000 ml of distilled water is added (pH 7.2 to 7.4)

Sterilization: 15 minutes at 120 ° C in autoclave

2. Glucose Juicy: Streptococcus Aaronson and Streptococcus Piogenes

The composition is the same as the meat extract juice.

After sterilization, 1% by weight of glucose is added as 50% sterilization solution.

3. Savourad gravy: Candida albicans, trichophyton metagrophytes, aspergillus niger

Composition: casein peptone 10g sodium chloride 1g

Glucose 40g Sodium Diphosphate (Na ₂ HPO ₄ ) 1g

Sterilization: 5 to 10 minutes at 120 ℃, pH is not constant.

[Standardization of Density of Microorganisms]

14mm, 필터 546nm)에 따른 광도계 및 1%염화바륨용액 3.0ml를 1% 황산 97ml에 가하여 만든 황산바륨의 대조용 현탁액을 사용하여 수행한다. 표준화한 후 박테리아는 염화나트륨 용액을 사용하여 1:1000의 농도로 더 희석하고, 진균류는 희석하지 않은 상태로 사용한다.The first incubation period is 24 hours for bacteria and 14 days for fungi. Standardization of microbial suspensions is based on Eppendorf

14 mm, filter 546 nm) and a control suspension of barium sulfate prepared by adding 3.0 ml of 1% barium chloride solution to 97 ml of 1% sulfuric acid. After normalization, the bacteria are further diluted to a concentration of 1: 1000 with sodium chloride solution and fungi are used undiluted.

Preparation of Compound Concentration

40 mg of compound is placed in a 10 ml volumetric flask and the solvent (dilution ratio 1: 2500 = 4000 µg / ml) is filled to the graduation. Dilution with distilled water or solvent further prepares the concentration of the compound as follows: 1000; 250; 62.5 μg / ml.

[Test operation]

Each test tube is filled with 4.9 ml of the corresponding liquid nutrient medium, and then 0.1 ml of the dilution of the compound prepared above is placed in each test tube to the final concentration mentioned above. Finally, each test tube is inoculated with 0.1 ml of a standardized suspension of microorganisms. Control tests using only solvents are performed simultaneously.

[Culture]

Bacteria are incubated at 37 ° C. for 18-20 hours, and fungi at 27 ° C. for 7 days.

[evaluation]

The minimum inhibitory concentration (minimal bacteriostatic concentration) is determined by checking with a bath.

Agar diffusion test:

Nutritional Medium

1.Meat Extract Agar: Staphylococcus Arureus SG 511

Composition: Peptone 10g Dibasic sodium phosphate (Na ₂ HPO ₄ ) 2g

Meat Extract 8g pronagar 15g

Add 1000ml of 3g sodium chloride distilled water (ph7.2-7.4)

Sterilization: 15 minutes at 120 ° C in autoclave

2. Clucose Agar: Streptococcus Aaronson and Streptococcus Piogenes

The composition is like a meat extract agar. After sterilization 1% by weight of glucose is added as a 50% sterile solution.

3. Savourad Agar: Cannada Albicans, Trichophyton Mentagro-Pites, Aspergillus Niger.

Composition: Casein 10 g Peptone 10 g Sodium Diphosphate (Na ₂ HPO ₄ ) 1 g

Cluj's 40g Pron Agar 15g

1 g of sodium chloride is added to 1000 ml of distilled water

Sterilization: 5-10 minutes at 120 ℃, pH is not constant.

[Standardization of Microbial Density]

14mm, 필터 546mm)에 따른 광도계를 사용하며 대조현탁액으로 1% 황산 97ml에 1% 염화바륨용액 3.0ml을 가하여 만든 황산 바륨을 사용한다.The first incubation period is 24 hours for bacteria and 14 days for fungi. Standardization of microbial suspensions is based on Eppendorf.

14mm, filter 546mm), and use barium sulfate prepared by adding 3.0ml of 1% barium chloride solution to 97ml of 1% sulfuric acid as a control suspension.

After standardization, Staphylococcus aureus SG 511 is diluted 1: 1000 with sodium chloride and Streptococcus pyogenes and Aaronson are diluted 1: 100. Fungi should be used undiluted.

Preparation of Compound Concentration

40 mg of compound is placed in a 10 ml volumetric flask and filled with a solvent (dilution ratio 1: 250 = 4000 µg / ml) to the graduation.

Dilution of the concentrate used in the test is carried out with distilled water or each solvent.

[Test operation]

19 ml of nutrient medium is placed in sterile Petri dishes with a diameter of 8 cm and dried. Subsequently, add agar ml for spawn to agar plate. Since 100 ml of spawn agar contains 1.25 ml of microbial suspension, agar plate contains 0.05 ml of microbial suspension. After solidifying the agar, a 5 mm diameter hole is made in the plate and filled with 0.05 ml of a solution of concentrated compound. Control tests using only solvents are performed simultaneously.

[Culture]

Bacteria are incubated at 37 ° C. for 18-20 hours, and fungi at 37 ° C. for 7 days.

[evaluation]

Subtract the diameter of the hole and measure the diameter of the suppression area in mm. Measurements are shown in parentheses for the areas where the growth was significantly reduced instead of the areas where there was no growth at all.

Serial dilution test for Corynebacterium acne and Pytirosporumovale

[Nutrition Badge]

Coryne Bacteria Acne: Thioglycolate-Juicy

Peter Rosporum Obare: Litman Juicy

5ml per test tube

[Density of microorganisms]

A suspension of microorganisms in a 0.9% sodium chloride solution standardized by a photometer according to Eppendorf using a control suspension consisting of barium sulfate is diluted 1: 100 for Corynebacterium acne and diluted for Pytirosporum obare 0.1 ml each of the suspension is added to the test tube. Dimethylsulfoxide is used as solvent for this compound. A suspension of Coryne bacteria acne is incubated for 48 hours at 37 ° C., and a suspension of Pytirosforum obare for 7 days at 20 ° C. Observe the microbial growth visually and measure the minimum inhibitory concentration.

Agar Diffusion Test for Phytirosporum Obare CBS 1878

[Nutrition Badge]

Litman Baby: 23 ml per Patridish with a diameter of 100 mm

[Density of microorganisms]

A control suspension of barium sulfate was used and 0.05 ml per agar plate was used for a suspension of microorganisms in a 0.9% sodium chloride solution normalized using a photometer according to Eppendorf.

Test substance is dissolved in dimethyl sulfoxide. Incubation time is 7 days at 27 ° C. and the inhibition area (mm) is measured.

0.05 ml of solution of test substance is filled into each hole 6 mm in diameter.

The results of these tests are reported in Tables 1 and 2 below.

TABLE 1

Gram-positive bacteria and Coryne bacteria activity against acne: MIC-Chi (ug / ml)

Numbers in parentheses indicate reduced growth at this concentration.

nt = not tested.

MIC = minimum inhibitory concentration

A.D.T = Agar Diffusion Test

S.D.T = continuous dilution test

TABLE 2

Activity against yeast, phytodermatological pathogens, fungi and phytophosphorum obare: MIC-Chi (ug / ml)

Determination of Glucose-6-Phosphate Dehydrogenase:

Equilibrium was observed:

글루콘산-6-포스페이트+NADPH+H⁺ Glucose-6-phosphate + NADP ⁺ +

Gluconate-6-Phosphate + NADPH + H ⁺

(NADP = Nicotinamide-Adenine-Deniglutide-Phosphate, G6P-H = Gluconate-6-Phosphate-Dehydrogenase)

Formation rate of NADPH is measured for enzyme activity. This can be measured as an increase in absorbance at 340, 334 or 336 nm per hour.

[Way]

To 0.025 ml of glucose-6-phosphate-dehydrogenase (only the Schinger group) is added distilled water and filled with 10 ml (solution I). 10 mg of nicotinamide-adenine-dinucleotide-phosphate is dissolved in 13 ml of distilled water (solution II). 47.2 mg of glucose-6-phosphate is dissolved in 10 ml of distilled water (solution III). At the same time, the buffer solution (solution IV) is prepared as follows. 0.28 g of trimethanolamine-hydrochloride and 1.46 g of ethylene diaminotetra acetic acid-disodium salt are dissolved in 1 L of distilled water and adjusted to pH 7.6 with sodium hydroxide solution. Test compound is dissolved in dimethylformamide or ethanol (solution V).

Concentrations used for the test: 50: 25: 12.5: 6.25: 3.125. 1.56 and 0.78 µg / ml.

[Measurement of Inhibitory Effect Immediately]

0.1 ml of Solution I, 0.1 ml of Solution II, 2.67 ml of Solution IV, and 0.03 ml of Solution V were mixed and allowed to stand at 25 ° C. for 5 minutes, then 0.1 ml of Solution III was added and mixed, and the absorbance was changed by spectrophotometer at 366 nm for 3 minutes. Measure

[Measurement of inhibitory effect after culture]

0.1 ml of solution I, 0.1 ml of solution II, 2.67 ml of solution IV, and 0.03 ml of solution V were mixed and left at 37 ° C. for 60 minutes, and then mixed with 0.1 ml of solution III and mixed for 3 minutes at 366 nm with a spectrophotometer. Measure

The inhibition value is calculated from the average value of the three measured values (change in absorbance per minute) compared to the control solution made of a pure solvent as the inhibitor solution.

ED ₅₀ is then the value calculated from the inhibition for various concentrations according to the method of read and ank.

TABLE 3 G6PHD-inhibition

Measurement of Cell Culture Inhibition

[Way]

Hera-cell culture is treated with trypsin and adjusted to contain 150,000 cells per ml in fresh medium. The compound is dissolved in the same amount of dimethylsulfoxide and then further diluted with growth medium. 0.1 ml of diluted compound is added to each hole of the microtiterplates, followed by 0.2 ml of cell suspension (4 holes per dilution).

Instead of 0.1 mole of diluting compound, several growth controls containing 0.1 ml of growth medium are made. After careful mixing, incubate at 37 ° C. for 3 days under 5% atmospheric pressure of carbon dioxide. The results are measured by comparison with these controls. The results are measured compared to the growth control. Results were measured as a percentage for reduction and alteration compared to the growth control. Minimum inhibitory concentrations were determined from these results and ED ₅₀ was calculated according to the Reed and Muenck method and expressed in μg of compound per ml of total medium. The results are reported in the following table.

TABLE 4

The compounds mentioned are chemically stable, exhibit good lipophilic action (distribution coefficient n-octanol / water> 1000) and can also be well incorporated into ointments, creams, tinctures, sprays, powders and the like suitable for topical use.

It has the advantages of good applicability to the skin (creams containing 10% of compound E which does not irritate for more than 24 hours under closed conditions) and low toxicity.

Acute toxicity was measured as a mouse.

LD _50, i.e. the amount of 50% lethality of animals within 14 days _, was calculated.

LD _{50 in} Mice:

Compound E Oral> 3,200 mg / kg Subcutaneous> 4,000 mg / kg Intraperitoneal 82 mg / kg

In general, pharmacological studies of compounds affecting major body functions, such as the heart / circulatory system or central nervous system, showed little effect. Therefore, systemic side effects from local use do not occur.

However, only a small amount is reabsorbed, as shown in the analysis of excretion because it has a good lipophilic action when the polar groups of the compounds that are well penetrated into the skin are present simultaneously.

Adaptation and sensitivity tests on the skin with molar moth showed that the introduction of trifluoro acetyl groups eliminated some susceptibility to resorcin. In some cases, this is very beneficial because resorcin, such as nucleisolcinol, causes allergies in humans.

Current effective treatments for acne are only systemic treatments with strong antibiotics (tetracycline, erythromycin) and locally peeling agents such as vitamin-A-acid and benzoyl peroxide.

The use of antibiotics in non life-threatening diseases results in the formation of resistance, and the use of skin removers requires significant irritation to the skin.

In the treatment of acne using antibiotics, Gram-positive bacteria, the main pathogen for acne, in particular the above or corynebacteria acne, are found in the sebum due to a decrease in the content of free fatty acids in sebum separated by triglycerides by these bacteria. Is reduced.

As shown in Table 1, the compounds described above have potent activity against Corynebacteria acne. In addition, it can be seen that after topical use, the content of free fatty acids can be significantly reduced. Therefore, local treatment is possible and comparable to the effect of oral administration of antibiotics.

The exact cause of hair dandruff is not known yet. However, keratosis is known as hair dandruff, for example, it promotes mitosis in the epidermis and additionally causes keratosis. Yeast phytirosporum obare has been shown to have hair dandruff production [R.A. Gosse, R. W. Vander Wyck, J. Soc. Cosmet. Chem 20, 603 (1969)].

Table 2 shows that some of the compounds described above exhibit potent action against Pytirosporum obare.

It can be seen from Tables 3 and 4 that these and other compounds can delay accelerated mitosis progression. Therefore, the treatment of hair dandruff allows the use of compounds exhibiting good action in Tables 2, 2 and 4.

Currently, effective treatment of dryness uses dislanol, tar and high activity adrenal cortex as a local treatment, and metabolic agents such as methotrexate, corticosteroids and cellular inhibitors are available for systemic treatment. . In addition, UV-light, X-ray physiotherapy and psotarene (systemic and local therapy) and UV-light are combined. All these therapies are accompanied by minor or significant side effects. Therefore, simple local therapy is beneficial. Tables 3 and 4 above and the compounds can be used to treat psoriasis (dandruff).

Diseases caused by filamentous fungi on the skin occur frequently. Separately, it is particularly beneficial to use antifungal agents that have a wide range of effects on dermatophytes, yeast and bacteria, since it is not possible to determine the type of microbe that causes the irritation.

It can be seen that the compounds described above in Tables 1 and 2 have potent activity against these microorganisms and thus can be used to treat filamentous fungi and bacterial dermatitis.

The following examples illustrate the invention.

Example 1

2,4-dihydroxy-5-n-nuclear-trifluorocetophenone

194 g of 4-n-hexyl resorcin (1 mole) is suspended in 3 L of ethylene chloride, followed by addition of 300 g (2 moles) of aluminum chloride with stirring in small portions at about 20 ° C. followed by 260 g (1.2 moles) of trifluoro. Acetic anhydride is added at 15-20 ° C. over about 1-1.5 hours and the mixture is cooled with ice water. After stirring for 3 hours the mixture is left for 1-2 days. To separate the mixture, add the mixture to 2.5 kg of ice with stirring (cool to not allow the temperature to rise above 25 ° C). The organic layer is separated off and the aqueous layer is washed three times with 500 ml of ethyl chloride. The organic layers were all washed with 1 L of water, dehydrated with calcium chloride and concentrated to recrystallize the residue obtained with heptane or petroleum ether.

Melting point: 90 ℃, yield: 246g (85% of theory)

The following compounds are prepared in a similar manner.

a) 2,4-dihydroxy-3-methyl-trifluoroacetophenone

Prepared from 2-methyllesolecin in ethylene chloride.

Melting point: 101 ° C, yield: 90% of theory

b) 2,4-dihydroxy-5-n-propyl-trifluoroacetophenone

Prepared from 4-n-propylresolecin in ethylene chloride.

Melting point: 95 ° C yield: 87% of theory

c) 2,4-dihydroxy-5-isopropyltrifluoroacetophenone

Prepared from 4-isopropylresolecin in chloroform.

Melting point: 97 ° C, yield: 70% of theory

d) 2,4-dihydroxy-3-n-propyl-trifluoroacetophenone

Prepared from 2-n-flophilesolcin in ethylene chloride.

Melting point: 114 ° C, yield: 88% of theory

e) 2,4-dihydroxy-3-isopropyl-trifluoroacetophenone

Prepared from 2-isopropylresolecin in ethylenechloride.

Melting Point: 145 ° C, Yield: 85%

f) 2,4-dihydroxy-5-n-butyl-trifluoroacetophenone

Prepared from 4-n-butylresolecin in ethylene chloride.

Melting Point: 96 ℃, Yield: 82%

g) 2,4-dihydroxy-5-isobutyl-trifluoroacetophenone

Prepared from 4-isobutyllesolcin in ethylene chloride.

Melting Point: 90 ° C, Yield: 84%

h) 2,4-dihydroxy-3-isobutyl-trifluoroacetophenone

Prepared from 2-isobutyllesolcin in ethylene chloride.

Melting Point: 114 ℃, Yield: 78%

I) 2,4-dihydroxy-5-tert-butyl-trifluoroacetophenone

Prepared from 4-tert-butyl resolcin in ethylene chloride.

Melting Point: 159 ℃, Yield: 80%

j) 2,4-dihydroxy-5- (2-methyl) -n-propyl-trifluoroacetophenone

Prepared from 4- (2-methyl) -n-propylresolecin in ethylenechloride

Melting Point: 90 ℃, Yield: 78%

k) 2,4-dihydroxy-5-N-pentyltrifluoroacetophenone

Prepared from 4-n-pentylesolecin in ethylene chloride.

Melting Point: 97 ° C, Yield: 86%

I) 2,4-dihydroxy-5-cyclopentyl-trifluoroacetophenone

Prepared from 4-cyclopentylesolecin in ethylene chloride.

Melting Point: 94 ℃, Yield: 75%

m) 2,4-dihydroxy-3-isopentyl-trifluoroacetophenone

Prepared from 2-isopentylesolecin in ethyl chloride.

Melting Point: 101 ° C, Yield: 84%

n) 2,4-dihydroxy-3-n-pentyl-trifluoroacetophenone

Prepared from 2-n-pentylesolecin in ethylene chloride.

Melting Point: 105 ℃, Yield: 87%

o) 2,4-dihydroxy-5-cyclohexyl-trifluoroacetophenone

Prepared from 4-cycloresorcin in ethylene chloride.

Melting Point: 80 ℃, Yield: 78%

p) 2,4-dihydroxy-5-n-heptyl-trifluoroacetophenone

Prepared from 4-n-heptylesolcin in ethylene chloride.

Fusion: 85 ℃, Yield: 79%

q) 2,4-dihydroxy-5-n-benzyl-trifluoroacetophenone

Prepared from 4-benzylesolecin in ethylene chloride.

Melting Point: 114 ℃, Yield: 80%

r) 2,4-dihydroxy-3- (4-methyl) -cyclohexyl-trifluoroacetophenone

Prepared from 2- (4-dimethyl) -cyclonucleosil-resorcin in ethylene chloride.

Melting Point: 143 ℃, Yield: 76%

s) 2,4-dihydroxy-5- (3,5-dimethyl) -cyclohexyl-trifluoroacetophenone

Prepared from 4- (4,5-dimethyl) -cyclohexylesolecin in ethylene chloride.

Melting Point: 126 ℃, Yield: 79 ℃

t) 2,4-dihydroxy-5-n-nonyl-trifluoroacetophenone

Prepared from 4-n-nonylesolecin in ethylene chloride.

Melting Point: 87 ℃, Yield: 85%

u) 2,4-dihydroxy-5-n-dodecyl-trifluoroacetophenone

Prepared from 4-n-dodecylesolecin in ethylene chloride.

Melting Point: 92 ℃, Yield: 84%

v) 2,4-dihydroxy-5-chloro-trifluoroacetophenone

Prepared from 4-chlororesolecin in ethylene chloride.

Melting Point: 110 ℃, Yield: 90%

w) 2,4-dihydroxy-5-bromo-trifluoroacetophenone

Prepared from 4-bromoresolecin in ethylene chloride.

Melting Point: 81 ℃, Yield: 88%

x) 2,3,4-trihydroxytrifluoroacetophenone

It is produced from a pyro roll.

Melting Point: 134 ℃, Yield: 75%

y) 2,4-dihydroxy-3-methoxy-trifluoroacetophenone

Prepared from 2-methoxy-resorcin in ethylene chloride.

Melting Point: 79 ℃, Yield: 78%

z) 2,4-dihydroxy-5- (2,2,3,3-tetrafluoro) -cyclobutylmethyl trifluoroacetophenone

Prepared from 4-tetrafluorocyclobutylmethyl-resorcin in ethylenechloride.

Melting Point: 122 ℃, Yield: 76%

aa) 2,4dihydroxy-5-methylthio-trifluoroacetophenone

Prepared from 4-methylthio-resolecin in ethylenechloride.

Melting Point: 57 ° C, Yield: 68%

bb) 2,3,4-trihydroxy-5-cyclohexyl-trifluoroacetophenone

Prepared from 4-cyclohexyl-pyrogarol in ethylenechloride.

Melting Point: 128 ℃, Yield: 78%

cc) 2,3,4-trihydroxy-5-ethyl-trifluoroacetophenone

Prepared from 4-ethyl-pyrogarol in ethylene chloride.

Melting Point: 82 ℃, Yield: 80%

dd) 2,4-dihydroxy-3-chloro-trifluoroacetophenone

Prepared from 2-chloro-resorcin in ethylene chloride.

Melting point: 113 ° C, yield: 83% of theory

ee) 2,4-dihydroxy-5-n-octyl-trifluoroacetophenone

Prepared from 4-n-octyl-resolecin in ethylene chloride.

Melting point: 87 ° C, yield: 74% of theory

ff) 2,4-dihydroxy-3-cyano-trifluoroacetophenone

Prepared from 2,6-dihydroxybenzonitrile in ethylene chloride.

Melting Point: 210 ℃, Yield: 62% of Theory

gg) 2,2,4,4'-tetrahydroxy-5,5'-ditrifluoroacetyl-diphenylsulfide

Prepared from 22 ', 4,4'-tetrahydroxy-diphenylsulfide in ethylenechloride.

Melting Point: 172 ℃, Yield: 10% of Theory

hh) 2,2 ', 4,4'-tetrahydroxy-5-trifluoroacetyl-diphenylsulfide

Prepared from 2,2'4,4'-tetrahydrooxy-diphenylsulfide in ethylene chloride.

Melting Point: 204 ℃, Yield: 20% of Theory

Example 2

2,4-dihydroxy-5-n-hexyl-trifluoroacetophenone

In a similar manner to Example 1, 19.4 g of 4-n-hexylsolecin is suspended in 300 ml of ethylene chloride and 27.2 g of zinc chloride are added. 25 g of trifluoroacetic anhydride is then added dropwise at 15 to 20 ° C. and left for 1 to 2 days before the mixture is treated in a similar manner as in Example 1.

Yield: 25.5 g (87% of theory)

Example 3

2,4-dihydroxy-5-n-hexyl-trifluoroacetophenone

In a similar manner to Example 1, 19.4 g of 4-n-hexylsolecin is suspended in 300 ml of ethylene chloride and 32.4 g of ferric chloride are added. Then 25 g of trifluoroacetic anhydride are added dropwise at 15 to 20 ° C. and the mixture is treated in a similar manner to Example 1.

Yield: 19.7 g (68% of theory)

Example 4

2,4-dihydroxy-5-n-hexyl-trifluoroacetophenone

In a similar manner to Example 1, 19.4 g of 4-n-hexylsolecin is suspended in 300 ml of ethylene chloride and 5 g of p-toluenesulfonic acid is added. Then 25 g of trifluoroacetic anhydride are added dropwise at 15 to 20 ° C. and treated in a similar manner to Example 1.

Yield: 7.6 g (22% of theory)

Example 5

2,4-dihydroxy-5-n-hexyl-trifluoroacephenone

In a similar manner as in Example 1, 19.4 g of 4-n-hexylenezoline is suspended in 300 ml of ethylene chloride and etherate is added to 15 g of borontrifluoride. 25 g of trifluoroacetic anhydride is then added dropwise at 15 to 20 ° C. and the mixture is treated in a similar manner to Example 1.

Yield: 17 g (60% of theory)

Example 6

2,4-dihydroxy-5-n-hexyl-trifluoroacetophenone

In a similar manner to Examples 1,4, 19.4 g of 4-n-hexylsolecin was dissolved in 150 ml of toluene and mixed with the catalysts listed in the following table, followed by the dropwise addition of 25 g of trifluoroacetic anhydride and the reaction mixture 1 To 2 days. The yield obtained is shown in the following table.

Example 7

2,4-dihydroxy-5-n-hexyl-trifluoroacetophenone

The reaction is carried out in a similar manner to Examples 1-4. The solvent uses 100 ml of nitrobenzene and the catalysts described in the following table. The obtained result is as follows.

Example 8

2,4-dihydroxy-5-n-hexyl-trifluoroacetophenone

In a similar manner to Examples 1-4, the solvent is used as the solvent in 100 ml of phosphorus oxychloride and the catalysts described in the following table. The obtained result is as follows.

The reaction is carried out at 100 ° C. in 2 hours.

Example 9

2,4-dihydroxy-5-n-hexyl-trifluoroacetophenone

The reaction is carried out in a similar manner to Examples 1-4, using 100 ml of ether as solvent and the catalysts listed in the following table.

Example 10

2,4-dihydroxy-5-n-hexyl-trifluoroacetophenone

In a similar manner to Examples 1-4, 300 ml of ethylene chloride, dissolved in 19.4 g of 4-n-hexyl-resolecin, was refluxed with 16 g of ethyl triluacetate per 10 hours in the presence of 10 g of p-toluene sulfonic acid. The mixture is treated in a similar manner to Example 1.

Melting Point: 90 ° C Yield: 7.4g (25% of theory)

In a similar manner the same compound can be prepared as follows:

4-n-hexylsolecin is refluxed for 5 hours using octyltrifluoroacetate as the acylating agent and boron trifluoride etherate as catalyst:

Yield: 5% of theory. The compound is 3% when p-toluenesulfonic acid is used as catalyst.

Example 11

2,4-dihydroxy-5-n-hexyl-trifluoroacetophenone

In a similar manner to Example 1, 30 g of aluminum chloride was added in small portions to 300 ml of ethylene chloride dissolved with 19.4 g of 4-n-hexylesolecin, followed by cooling of 15 g of trifluoroacetyl chloride dissolved in cooled ether with ice. While adding. The reaction mixture is left for 1 to 2 days and then treated in a similar manner as in Example 1.

Melting point: 90 ° C, yield: 26.9g (92% of theory)

Example 12

2,4-dihydroxy-5-n-hexyl-trifluoroacetophenone

In a similar manner as in Example 11, 4-n-hexylesolecin is reacted with trifluoro acetylchloride in the presence of the solvent and catalyst described in the following table.

Example 13

2,4-dihydroxy-5-n-hexyl-trifluoroacetophenone

Dissolve 19.4 g of 4-n-hexylesolecin in 300 ml of ethylene chloride and add 50 g of phosphorus pentoxide in small portions.

14 g of trifluoro acetinic acid was added to the mixture, and the mixture was left for 1-2 days and treated in a similar manner as in Example 1.

Melting point: 90 ° C, yield: 15.6g (54% of theory)

When p-toluenesulfonic acid is used instead of phosphorus pentoxide as a catalyst, the yield is 30%, and the yield is 40% when refluxed for 2 hours using borontrifluoride etheride.

Example 14

2,4-dihydroxy-5-n-hexyl-trifluoreacetophenone

In a similar manner as in Example 12, refluxing 4-n-hexylesolecin with trifluoro acetate amide as the acylating agent and boron trifluoroetherate as the catalyst for 5 hours gave 55% of the title compound. Obtained in yield. When p-toluenesulfonic acid is used as a catalyst, a yield of 20% is obtained.

Refluxing 4-n-hexyl-resolecin for 5 hours using trifluoropropylamide as an acylating agent and boron trifluoride etherate as a catalyst yielded the same compound in 15% yield and p-toluenesul as catalyst Use of phonic acid yields a yield of about 5%.

Example 15

2,4-dihydroxy-5-n-hexyl-perfluoropropiophenone

In a similar manner to Example 1, 1.94 g of hexylesolecin is mixed with 30 ml of ethylene chloride and 3 g of aluminum chloride, and 3.6 g of perfluoropropionic anhydride is added. After stirring for 1-2 days at room temperature the mixture is treated in a similar manner to Example 1.

Yield: 70% of theory, Melting point: 62 ° C

In a similar manner the following compounds are prepared.

a) 2,4-dihydroxy-perfluoropropiophenone

It is prepared from resorcin.

Melting Point: 80 ℃, Yield: 72% of Theory

b) 2,4-dihydroxy-3-methyl-perfluoropropiophenone

It is prepared from 2-methyllesolecin.

Melting point: 69 ° C, yield: 76% of theory

c) 2,4-dihydroxy-5-methyl-perfluoropropiophenone

Prepared from 4-methyllesolecin.

Melting point: 140 ° C, yield: 75% of theory

d) 2,3,4-trihydroxy-perfluoropropiophenone

It is produced from a pyro roll.

Melting point: 105 ° C, yield: 760% of theory

Example 16

In a similar manner to Example 15, the following compounds are prepared from perfluorobutyric anhydride.

a) 2,4-dihydroxy-perfluorobutyrophenone

It is prepared from resorcin.

Melting point: 90 ° C, yield: 66% of theory

b) 2,4-dihydroxy-3-methyl-perfluorobutyrophenone

It is prepared from 2-methyllesolecin.

Melting Point: 75 ℃, Yield: 65% of Theory

c) 2,4-dihydroxy-5-n-hexyl-perfluorobutyrophenone

It is prepared from 4-n-hexylesolecin.

Melting point: 57 ° C, yield: 60% of theory

Example 17

2,4-dihydroxy-5-n-hexyl-perfluoropropiophenone

To 30 ml of ethylene chloride dissolved in 1.94 g of 4-n-hexylesolecin, boron trifluoride etherate and 2.2 g of perfluoro propionic acid were mixed and refluxed for 5 hours and treated in a similar manner to Example 1.

Melting Point: 62 ℃, Yield: 1.4g (41% of Theory)

In a similar manner the following compounds are prepared.

2,4-dihydroxy-3-methyl-perfluorocaprylophenone

It is prepared from 2-methyllesolecin.

Rf-value 0.87 (Solvent: Petroleum ether: Chloroform: Ethyl acetate (3: 6: 1)

Example 18

2,4-dihydroxy-3-methyl-trifluoroacetophenone-monoacetate

4.4 g (0.02 mole) of 2,4-dihydroxy-3-methyl-trifluoroacetophenone is dissolved in 25 ml of benzene and 3.2 (0.04 mole) of acetylchloride and 3.6 g (0.045 mole) of pyridine are stirred While adding. After stirring for 2 hours at room temperature, the mixture is poured into water and the benzene layer is separated. The solution is washed with 50 ml of water and dehydrated with sodium sulfate. The residue obtained by evaporation in a rotary concentrator is recrystallized in n-hexane.

Melting Point: 49 ~ 50 ℃, Yield: 4.5g (86.5% of Theory)

In a similar manner the following compounds are prepared.

2,4-Dihydroxy-5-chloro-trifluoroacetophenone-monoacetate

It is prepared from 2,4dihydroxy-5-chloro-trifluoroacetophenone and acetylchloride.

Melting point: 80-83 ° C., yield: 71,5% of theory

2,4dihydroxy-5-chloro-trifluoroacetophenone-monostearate

It is prepared from 2,4-dihydroxy-5-chloro-trifluoroacetophenone and stearoylchloride.

Melting point: 51 ° C, yield: 40% of theory

2,4-dihydroxy-3-methyl-trifluoroacetophenone-monoundecynate

It is prepared from 2,4-dihydroxy-3-methyl-trifluoroacetophenone and 11-undecylene acid chloride and the compound is purified by distillation.

Boiling Point: 0.07 = 165C, Yield: 64% of theory

2,4-Dihydroxy-5-chloro-trifluoroacetophenone-monoundecynate

Prepared from 2,4-dihydroxy-5-chloro-trifluoroacetophenone and 11-undecylene acid chloride

This compound is purified by distillation.

Boiling point: 0.07 = 168 ° C., yield: 65% of theory

2,4-Dihydroxy-5-hexyl-trifluoroacetophenone-monoacetate

Prepared from 2,4-dihydroxy-5-hexyl-trifluoroacetophenone and acetylchloride.

Melting Point: 30 ℃, Yield: 83% of Theoretical Value

2,4-Dihydroxy-5-hexyl-trifluoroacetophenone-monostearate

Prepared from 2,4-dihydroxy-5-hexyl-trifluoroacetophenone and stearoylchloride.

Yield: 77% of theory

2,4-dihydroxy-3-methyl-trifluoroacetophenone-di-phenylacetate

It is prepared from phenylacetyl chloride and 2,4dihydroxy-3-phenyl-trifluoroacetophenone.

Melting Point: 65 ℃, Yield: 90% of Theoretical Value

Example 19

Mono and disalicylate mixtures of 2,4-dihydroxy-3-methyl-trifluoro-acetophenone

32 g of dartium salicylate and 2.2 g of 2,4-dihydroxy-3-methyltrifluoroacetophenone are dissolved in 20 ml of benzene, added to 3.2 g of phosphorus oxychloride, and then the mixture is stirred for 2 hours. Reflux for a while. The mixture is poured into 150 g of ice to decompose the phosphorus oxychloride and the benzene layer is separated. The aqueous layer is extracted with 50 ml of benzene, the combined benzene solvents are washed with 100 ml of water, dehydrated with dartium sulfate and evaporated to recrystallize the residue from 75% methanol.

Melting Point: 94-98 ℃, Yield: 40% of Theoretical Value

It was found to be a mixture of mono- and dissalicylates in the UV-, IR- and NMR-spectrums.

Example 20

a) 10.3 g (0.05 mol) of 2-hydroxy-4-decyloxy-trifluoroacetophenone and 2,4-didecyloxy-trifluoroacetophenone 2,4-dihydroxy-trifluoro Acetophenone is refluxed with 7 g (0.05 mol) of potassium carbonate (anhydrous), 26.8 g (0.1 mol) of decyliodide and 100 ml of acetone for 5 hours. Acetone is then evaporated in a rotary concentrator and 100 ml of water are added to the residue. The mixture is extracted with 100 ml of ethyl acetate and the solution is dehydrated with dartium sulfate. After evaporation in a rotary concentrator the mixture is distilled off and separated into mono- and diethers. Unreacted decyl iodide is obtained at a boiling point of 0.1 = 80 ° C. The ether is recrystallized from methanol.

Monoether: boiling point 0.1 = 150 ° C., melting point: 27 to 28 ° C., yield: 9.2 g (53.2% of theory)

Diether: boiling point 0.1 = 200 ℃, melting point: 37-38 ℃, yield: 5.6g (23.0% of theory)

In a similar manner the following compounds are obtained.

2-hydroxy-4-butoxy-trifluoroacetophenone

2,4-dihydroxy-trifluoroacetophenone

Melting point: 66 ° C, yield: 28.5% of theory

2,4-dimethoxy-5-n-hexyl-trifluoroacetophenone

Melting point: 52 ° C, yield: 30.5% of theory

b) 2,4-dimethoxy-trifluoroacetophenone

75 g of 3 g (0.015 mol) of 2,4-dihydroxy-trifluoroacetophenone dissolved in 75 ml of methylene chloride and 0.6 g (0.002 mol) of tetrabutyl ammonium bromide and 2 g of dartium hydroxide in this solution An aqueous solution of and 5 g (0.04 mol) of dimethylsulfate are added. After stirring vigorously for 5 hours, the mixture is poured into 100 ml of water, acidified with 15% hydrochloric acid, the organic layer is separated, dehydrated with dartium sulfate, and evaporated to recrystallize the residue obtained with n-pentane.

Melting Point: 49 ℃, Yield: 2g (57% of Theory)

The compound of formula (1) may be mixed with conventional pharmaceutical preparations, namely foam aerosols, powder-spraying agents, powders, throat sprays, shampoos, creams, ointments, tinctures, pastes or gels. The dose of active ingredient is 0.05 to 1% by weight, preferably 0.1 to 0.8% by weight.

For the use of plant protection agents the compounds according to the invention can be made into conventional preparations, in particular solutions or emulsion concentrates, powders, granules, powders for spraying, powders for seed treatment and solutions.

The active substance content in the powder and powder for spraying is 0.01 to about 3% by weight. Seed solutions (about 10 to 50% by weight) and seed treatment powders (about 20 to 90% by weight) as well as concentrates (about 95% by weight) contain higher concentrations of the active compound.

Seed treatment formulations are sprayed (solution state) or mixed with seeds (powder state). This compound is used in particular to control genus Thieletia, Helmintosporum, Eustigo and Fusarium fungi.

Claims (1)

Characterized in that the resorcin of formula (II) or a derivative thereof is acylated with a carboxylic acid of formula (III) or a reactive derivative thereof in the presence of Friedel-Craft-catalyst and a solvent at a boiling point of from -80 ° C Next, the method for producing fluoroacylsolecin of general formula (I).

In the general formula, R ₁ represents a perfluoroalkyl group or 2,2,3,3-tetrafluorocyclobutyl group having 1 to 8 carbon atoms, R ₂ and R ₄ are the same or different from each other, a hydrogen atom, 1 to 10 carbon atoms Linear or branched alkyl group, aliphatic acyl group having 2 to 18 carbon atoms, benzoyl, salicyloyl, or panylacetyl group, and R ₃ and R ₅ are the same as or different from each other and are alkyl group having 3 to 18 carbon atoms, halogen atom, nitro group or P-toluenesulfonyl group, cyclopentyl, cyclohexyl, cycloheptyl, cyclododecyl, methylcyclohexyl, dimethylcyclohexyl, benzyl or methylthio group, or a group of the following general formula

Wherein F represents a —CH ₂ — or —S— group when G is R ₅ or a R ₃ group when G is —CH ₂ — or —S—, and R ₁ , R ₃ and R ₄ are as defined above As defined and R ₃ also represents a hydroxy, methoxy, methyl or cyano group and R ₅ also represents a methyl group. However, 1) as defined above, except that one of the groups R ₃ and R ₅ is hydrogen, 2) as defined above except that R ₁ is a trifluoromethyl group, or 3) R ₃ and R ₅ as defined above, except that R ₂ and R 4 are hydrogen or a methyl group The other may represent a hydrogen atom or an ethyl group, and Y is a hydroxy or amino or acyloxy or alkoxy group or a halogen atom.