SU385441A1 - METHOD OF OBTAINING DERIVATIVES OF PHENYLACETIC ACID - Google Patents

Description

This invention relates to a process for the preparation of new phenylacetic acid derivatives of general formula I C - COOH where X is an oxygen or sulfur atom, R is a linear or branched alkylidene containing from 1 to 4 carbon atoms, Hal-chlorine, bromine or fluorine, as well as complex the esters of these 1slots 1 or their salts, which have valuable pharmacological properties and can be used in medicine as a pharmaceutical first drug. Known is the method of producing halo-phenylacetic acid by reacting a halo-substituted; benzyl halide / s- (an alkali metal anide and subsequent hydrolysis of luchroen nitrile to the halo-substituted phenylacetic acid. However, there are no data in the literature on the preparation of compounds of general formula I by the use of the general population of the general formula I, by the use of the same numbers, by the use of the numbers, the countries, and the same countries, will also be in a case, they will be given, they will be the same, the numbers of the general formula I, will be given by the applicable population of the general formula I, they will have the same numbers, the numbers of the general formula I, will not be affected by the numbers of the general formula I, we will be given, we will be given the numbers of the general formula I, we will be, we will be in a situation, we will not get phenylacetic acid derivatives of the general formula I, as well as esters of these acids or their salts, implying that, And Inonii general formula wherein X has the abovementioned meaning, is subjected to acid adetilirovaniyu -iroizvodnym RI-COOH wherein RI-linear or branched al; kilny radical containing from I to 4 carbon atoms in the presence of a Lewis acid, and the resulting three formupy Compound III

treated with nitrating reagent to obtain compounds of formula IY

CO-R,

where X is an oxygen atom or atoms of oxidized sulfur,

RI is as defined above, which is then treated with a reducing agent to form a compound of formula V

"Which with (HELP diazonium salts are converted to a compound of formula VI

lde Hal is a bromine, chlorine or fluorine atom,

X and RI are as defined above.

then process this halogenated

hydroanilic acid and

get the compound of formula VII

As an acetylating agent, it is preferable to use. ACID PRODUCTIVES

RI-COOH, such as chloride, bromide or acid anhydride.

The reaction of hydrocyanic acid with the compound of formula VI is carried out in the presence of a tertiary base, such as pyridine or lutidna. The conversion of anhydride of formula VII into the corresponding acid of Formula VIII by hydrolysis can be carried out in one or in two stages with the isolation and intermediate O: formation of amide.

The last stage of the process is the dehydration of an acid of formula VIII to obtain

the corresponding α-alkyl deoxy acids of the formula I are carried out using a dehydrating agent, for example sulfuric acid, phosphoric acid, phosphoric anhydride or, preferably, p-toluenesulfonic acid.

The desired product is isolated in the form of an acid, salt or ester. The conversion of 1 acids into the corresponding salts or esters is carried out according to known methods, regardless of whether you wish to obtain a salt with mineralization, in particular caustic soda or caustic ali, or with organic axis, such as triethylamine.

Diazomethane is preferably used as the esterification reagent to prepare the ester of these acids.

Example. Preparation of a-methylene-4- (4-tetrahydropyranyl) -3-chlorophenylacetic acid-Hal

Ri

- C - CIS OH

hydrolyzing it and get an acidic compound | formula VIII

which is subjected to the action of a dehydrating agent, followed by isolation of the target (Product in the form of acid, salt or ester in a known manner.

As Lewis acid, aluminum chloride, zinc chloride, tin chloride (IV), tin or boron trichloride are preferably used.

Concentrated nitric acid can be used as a nitrating agent, but a mixture of nitric and sulfuric acids is preferred.

As a reducing agent, it is possible to use a metal, such as: iron, tin, or zinc in the presence of an aqueous acid solution, for example, hydrochloric acid. Preferably, tin dichloride and coicentric hydrochloric acid are used.

you.

A. 4- (4-Tetrahydropyranyl) -acetophenone. 189 g of aluminum chloride are introduced in a 450 ml chloride methane at 10 ° C in a suspended state, and then 45 cm acetyl chloride is added over 5 minutes.

Next, a solution of 90 g of 4- | phenyltetrahydroopiraia is 250 ml of methylene chloride and, nazhoiets, 90 cm of methylene chloride; move 2 hours at 10 ° C, and then 4 hours at a room temperature. After that, 144 cm of hydrochloric acid are introduced into 820 cm of water, the organic layer is deactivated, the aqueous layer is extracted with methylene chloride, the combined organic layers are washed with water and then with a saturated aqueous solution of sodium hydrogencarbonate and, finally, with water. It is further formed over sodium sulfate and evaporated to dryness in a vacuum. The residue is dissolved in a warm state of 115 g

isopropyl ether, freeze overnight, filter by dilution with IPO, the precipitate is washed with ice with isopropyl ether and it is present in vacuum. Obtain 81.2 g of 4- (4-tetrahydracyrail) -a, ceto-phenone (yield 72%),

melting at 79-80 ° C, which is used in the next phase.

For analysis, the compound is recrystallized in isopropyl ether with heating and in the cold: 4- (4-tetrahydropyrayl) asthetofenone has the appearance of colorless crystals.

soluble in methyl alcohol and in methylene chloride, insoluble in water, melting at 80 ° C.

Analysis: CisHieOs. Mol weight 204.26.

Calculated,%: C, 76.44; H 7.90.

Naidio,%: C 76.2; H 7.5.

The NMR spectrum confirms the position of the laser. IR Spectrum - chloroform: the presence of a negative ketone at 1679 cm, COCH3 at 1360 g), an aromatic compound at 1608 and 1573 cm.

B. 4- (4-Tetrahydrapyranyl) -3-nitroacetophenone.

20 g of 4- (4-tetrahydropyranyl) -acetophenone are dissolved in 100 cm of sulfuric acid and the solution is cooled to -10 ° C; Add 20 cm of nitric acid (acid (density, 1.49) for 2 hours, incubate for 1 hour and 15 minutes at -10 ° C, pour the solution into an ice-water mixture with stirring and under a nitrogen atmosphere. Extract the chloride. m. washed with water, a saturated aqueous solution of sodium hydrogen carbonate and then with water to neutrality of the wash water, then dried over sodium sulfate and evaporated in vacuo to dryness. 23.18 g of crude 4- (4-tetrahydropyranyl) are obtained ) - 3-nitroacetophenone (95% yield), melting temperature about 70 ° C.

For the analysis, 2.4 g of the compound is recrystallized in methanol and heated and in cold. 1.15 g of 4- (4-tetrahydropyranyl) -3-nitro-1-acetophenoia is obtained. The compound has the form of light brown crystals, soluble in the hot state in chloroform, methylene chloride and alcohols, insoluble in water, Melting, at 78 ° C.

Analysis: Ci3Hi5NO4. Mol weight 249.26.

Calculated,%: C 62.64; H 6.07; N 5.62.

Found,%: C 62.6; H 5.9; N 5.5.

IR spectrum - chloroform: presence

COCH3 At 1696 NO2; at 1534 and 1357, as well as an aromatic compound substituted by a heteroatom.

B. 4- (4-Tetrahydropyrayl) -3-amino-istestophenone.

35 g of 4- (4-tetrahydropyranyl) -3-nitroacetophenone are introduced into 290 cm. Of hydrochloric acid, 98 g of tin dichloride are added and the reaction mixture is heated at 1 ° C at 60 ° C for 6 hours. Then it is allowed to cool to room temperature and left overnight with stirring, after which it is treated with ice for 30 minutes, filtered under vacuum. A. The residue is washed with water and introduced in suspension in 300 cm 2 and. caustic patra, incubated for 4 hours with stirring at 25 ° C, filtered with a vacuum under vacuum, washed with WATER and dried in vacuum. 24.7 g of 4- (4-tetrahydropyranyl) -3-amino-acetophenone are obtained, melting at 164 ° C, which is used in the next phase.

For analysis, 820 mg of the compound is recrystallized in methanol in a hot and cold state. 570 mg of 4- (4-tetrapidropyr "yl) -3-amino-acetophenone are obtained in the form of ocher crystals, soluble in the hot state in chloroform and alcohols, insoluble in water, melting at 164 ° C. Analysis: Ci3Hi7NO2. Mol weight 219.17.

Calculated,%: C, 71.20; H 7.82; N 6.39. Found,%: C 71.1; H 7.5; N 6.7. IR spectrum - chloroform: presence of NH2 at 3475 and 3395, COCH3 at 1675 and 1357 sl-1.

G. 4- (4-Tetrahydropyranyl) -3-chloroethophenone.

A three-necked flask was injected with a mixture consisting of 1440 cm of water and 900 cm of hydrochloric acid, which was cooled to 10 ° C, and 89.8 g of 4- (4-tetrahydropyranyl) 3-aminoacetophenone, the mass is cooled to 5 ° C and a solution of 29.25 g of sodium nitrite is poured

55 cm of water; transfer 30 minutes, maintaining the temperature at 5 ° C, slowly add a solution of 119 g of copper monochloride in 2070 cm of hydrochloric acid and leave the reaction mixture at room temperature overnight at

stirring, then filter under vacuum, wash the precipitate with water and dry in vacuo. 71.76 g of crude 4- (4-tetrahydropyranyl) -3-chloro of cetofenone are obtained, melting at 57 ° C, which is purified by shercrystallization in isopropyl ether, in a hot and cold state.

Thus, 46.4 g of a pure compound is obtained, which has the form of occlusive crystals, soluble in alcohol and chloroform, insoluble in water, melting at 59 ° C (yield 47%). Concentrate stock solutions, additionally collect 7.7 g of tro.duct, t. Pl. 59 ° C. yield (total) 55%. Analysis: Ci3Hi5ClO2. Mol weight 238.71.

Calculated,%: C 65.41; H 6.33; C1 14.85. Found,%: C 65.2; H 6.2; C1 14.5. IR spectrum - chlorofor.m: the presence of conjugated ketone at 1688, COCH3 at 1356, as well as an aromatic compound.

Similarly, according to known methods, the result from 4- (4-tetrahydropyranyl) -3-amino-1 acetophenone is obtained by decomposition of the corresponding methyl bromide

copper (I) - 4- (4-tetrahydropyrayl) -3-bromo-ischethophenone; thermal decomposition of the corresponding fluoroborate of the diazonium - 4- (4 tetragi Dropyranyl) -3-fluoroacetophenone.

D. a-Oxy-a-methyl-4- (4-tetrahydropyranyl) -3-chlorophenylacetamide.

5 cm of anhydrous hydrocyanic acid are cooled to 0 ° C. A solution of 5 g of 4- (4-tetrahydro.pyrapyl) -3-chloroacetophenone in 5 cm of pyridine is added and the mixture is stirred for 16 hours 1P | 3 ° C, then 55 cm of concentrated is added salt 1K1I1SLOTY, 25 cm of ether, then hydrogen chloride (gas) is doused for 24 hours at a comet temperature, Stirring. Next, the mass is poured into a mixture of ice water, the residue is extracted with ether containing 10% methylene chloride, the solution is washed with water, a saturated aqueous solution of sodium hydrogen carbonate and again with water to neutrality of the syrup water, dried "hell with sulfuric acid and sodium and evaporated to dryness in a vacuum. The residue was transformed into a pasty state in 50 cl of isoprolyl ether, stirred until complete crystallization at room temperature and filtered under vacuum. The precipitate is washed with mopropyl ether and dried in vacuo. 2.7 g of a-hydroxy-a-methyl-4- (4-tetrahydro-pyra-ylnyl) -3-chloro-phenyl acetamide are obtained in the form of crystals, soluble in alcohols, insoluble in methylene chloride, insoluble in water, melting at 135 ° C. This compound is used in the next phase. IR Spectrum - liquid paraffin: the presence of carbonyl at 1680 hedgehog, an aromatic compound, absorption about 3 microns (OH) NH. E. sb-Oxy-a-methyl-4- (4-tetrahydrapyranyl) -3-chlorophenylacetic acid. 3.4 g of caustic soda is dissolved in 34 cm of water and 34 cm of ethanol, 2.7 g of a-hydroxy-methyl-4- (4-tetrahydrapyranyl) -3-chlorophenyl chloroamide are added and the mixture is heated under reflux for 18 hours. The ethanol is distilled at atmospheric pressure, filtered hot, the solution is allowed to cool to room temperature and the pH is adjusted to 1 45 cm 2 n. hydrochloric acid, then the precipitated fraction is extracted four times with methylene chloride, the chloromethylene layers are washed with water until neutrality of the irradiated water, dried over sodium sulfate, and evaporated to dryness in vacuo. 2.7 g of a-hydroxy-methyl-4 - (4-tetrahyd | roT1-ylnyl) - 3-chlorophenyl acetic acid are obtained in the form of colorless crystals, soluble in hot form. In alcohols, insoluble in chloroform, insoluble in water, melting, 167 ° s For analysis, the product is recrystallized in ethanol hot and cold: as the fusion point does not change. Analysis: CuHieCU. Mol weight 284.74. Calculated,%: C 59.05; H 6.02; C1 12.45. Found,%: C 58.8; H 6.1; C1 12.6. IR Spectrum - vaseline oil: the presence of an aromatic compound, carbonyl at 1731 s / i-1, absorption in the OH band. G. Methylene-4- (4-tetrahydrapyranyl) -3 chlorophenyl acetic acid. A mixture consisting of 1.9 g of a-axi-a-methyl-4 (4-tetrahydropyranyl) -3-chlorophenyl acetic acid and 0.45 2 l-toluenesulfonyl acid in 190 cm of toluene is heated under reflux in an apparatus with azeropic separation of water 5 hours The reaction mass is then brought to room temperature, the toluene layer is washed with water, dried over sodium sulfate and evaporated to dryness in a vacuum. The residue is transformed into a IB dough into 30 squeezes of isopropyl ether. Under stirring, frozen for 1 hour, filtered under vacuum and dried in vacuo. 1.7 g of α-methylene-4 (4-tetrahydro-pyranyl) -3-chlorophenylacetic acid are obtained in the form of colorless crystals, soluble in chloroform and in alcohols in a hot state, insoluble in water, melting at 149 ° WITH. MiK-C neKTp - chloroform: no - OH, the presence of iri 891 cm at, 1617 cl -1. iO method and method of producing phenyl acetic acid derivatives of general formula I V-C-COOH where, X is an oxygen or sulfur atom, R is a linear or branched alkylidene, containing from 1 to 4 carbon atoms, Hal is a chlorine, bromine or fluorine atom, as well as} esters of these acids or their salts, characterized in that the compound of the general form II Form X has the above meaning, is subjected to acetylation by an acid derivative RI-COOH, where Ri is linear or branched alkyl radical, bulging from 1 to 4 carbon atoms, in the presence of acids the LIUIs, and the compound of formula III thus obtained, rV-iO - R, is treated with nitrating reagent to obtain the compound of formula IV de Xi - oxygen atom or oxidized sulfur atom. Ri is as defined above, which is then processed / reduced by the body to give a compound of the formula V " Hg

-CO-R, but with the help of Sol Diazoni translate Yu IB compound of formula VI

where Hal is a bromine, chlorine or f фur atom,

X and RI are as defined above.

then this cyanion compound is treated

which is controlled by the action of a dehydrating agent with the Subsequent isolation of the target product in iDI acid, salt or ester in a known manner. hydrochloric acid and get the compound of formula VII Hal R, x VC-CN hydrolyzing it and get the compound of formula VIII Hal R.