SU493969A3 - The method of obtaining esters of cinnoline carboxylic acids - Google Patents

Description

In the case when the acid of formula II is reacted with a compound of formula P1, the process is carried out in the presence of an acid catalyst. Inorganic or organic acids or acidic ion exchange resins are used as the acid catalyst. Hydrogen chloride, polyphosphoric acid, sulfuryl chloride or boron trifluoride are used as inorganic acid. L-toluenesulfonic acid and sulfosalicylic acid are used as organic acids. Ceo-Carb, H + -form (Ceo-Carb brand name) is used as acidic ion exchange resins. In the case when the compounds of the formula I have sufficiently basic properties, then salts of inorganic or organic acids are obtained: hydrochlorides, hydrobromides, tartrates or citrates. In the case when the compounds of the formula I possess sufficiently acidic properties, pharmaceutically acceptable salts are obtained: ammonium, alkali, alkaline earth, aluminum salts, or salts of organic bases: piperidine, triethanolamine or ethylene amine. Preferred are compounds of formula I, where R is an alkoxy group with 1-6 carbon atoms, a benzene ring A contains from one to four alkyls with 1-5 carbon atoms or a salt thereof. Particularly preferred of these are compounds where one substituent is contained - alkyl with 1-5 carbon atoms in position 6. Also preferred are compounds of formula I, where R is an alkoxy group with 1-6 carbon atoms, the benzene ring A is replaced by phenyl, which may itself be substituted with one to three substituents selected from alkyl with 1 to 3 carbon atoms, alkoxy groups with 1 to 3 carbon atoms, nitro groups, or halogen atoms. Particularly preferred are those in which the phenyl is substituted in position 6. Also preferred are compounds of the formula I, where R is an alkoxy group with 1-6 carbon atoms, the benzene ring A is substituted in the - 6 position by phenyl, which itself can be substituted one to three substituents selected from alkyl with 1-3 substituents, alkoxy groups: 1-3 carbon atoms, nitro groups or halogen atoms and, moreover, the benzene ring A may contain from one to three substituents selected from alkyl with 1 to 5 atoms carbon cycloal Kils, alkoxy groups with 1-5 carbon atoms or halogen atoms or their salts. The carboxylic acids used as starting compounds are obtained by the following reactions; )., I hydrolysis (for example, using NaOH) (C02I) PXs or SOXs (X is chlorine or bromine) (MOR). Fridel-Crafts catalyst (for example, TiCU) Example 1. Dry hydrogen chloride is bubbled through suspension 4- hydroxy-6-phenylcinnol-3-carboxylic acid (0.60 g) in boiling anhydrous ethanol (25 ml). Over a period of 20 minutes, a clear red solution is formed. This solution is heated for another 4 hours and then cooled and poured into water (100 ml) containing potassium acetate (25 g). The suspension is filtered and the residue is washed with water and crystallized from 40% aqueous ethanol (50 ml) to obtain white crystals of ethyl 4-hydroxy-6-phenylcinnolin-3-carboxylate; m.p. 257-259 ° С (with decomposition). The carboxylic acid used as the starting material was obtained as follows. A mixture of α-phenylphenylhydrazone of mesoxalic acid chloride (12.0 g), titanium tetrachloride (4.8 ml) and nitrobenzene (70 ml) is heated for 2 hours for a steam bath. After cooling, this mixture is poured into 3N. sodium hydroxide solution (125 ml). The suspension is moved for 30 minutes and then filtered. The residue is suspended in 2N. sodium hydroxide solution (60 ml), stirred for 15 minutes and filtered again. The combined filtrates are washed with diethyl ether (2X100 ml). The aqueous layer is stirred for 1 hour with activated charcoal (2 g) and then filtered. The filtrate is heated to about 80 ° C and acidified with concentrated hydrochloric acid until the pH is 1. The resulting yellow precipitate is filtered, washed with water, crystallized from the mixture, demethylformamide (80 ml) and with water (80 ml) is obtained 4-hydroxy-6- Phenylcinolyn-3-carboxylic acid as a light yellow powder; m.p. 278-279 ° С (with decomposition).

The phenylhydrozoa used as starting material is prepared as follows.

A solution of potassium hydroxide (49.5) in ethanol (200 ml) is added to a stirring suspension of n-phenylhydrazone diethyl mexoxalate (90 g) in ethanol (300 ml). After stirring at room temperature for 15 minutes, water (250 ml) was added and the mixture was stirred for 2 hours. The solution is diluted with water (750 ml), washed with methylene dichloride (3X250 ml) to remove the resinous suspension, and the aqueous layer is filtered and acidified by adding concentrated hydrochloric acid until the pH is below 1. The resulting thick yellow suspension is stirred for 15 min, then filtered, and the residue is washed with water. The solid yellow product is re-suspended in water (200 ml) and ethanol (20 ml). Concentrated aqueous ammonia (specific gravity 0.880, 10 ml) was added and the suspension was stirred for 30 minutes. Activated carbon (1 g) is added and the suspension is stirred for 15 minutes and then filtered. The filtrate is cooled with ice and acidified with concentrated hydrochloric acid until the pH is below 1, due to which a yellow precipitate is formed. This precipitate is filtered off, washed with water and dried to obtain the mesoxalic acid p-phenylphenylhydrazone; m.p. 198-199 ° C (after slight decomposition at 170 ° C and above).

A mixture of p-phenylphenyl hydrazone mesoxalic acid (5.1 g), phosphorus pentachloride (8.5 g) and benzene (50 ml) was heated at reflux on a steam bath for 45 minutes. The dark colored solution is diluted with petroleum ether (boiling point 40-60 ° C), then cooled, and the resulting orange solid is filtered and washed with petroleum ether (boiling point 40-60 ° C) to obtain m-phenylphenylhydrazone of mesoxalic acid chloride; m.p. 157-158 ° С (with decomposition).

EXAMPLE 2 Hydrogen chloride is bubbled through a suspension of 4-hydroxy-6-n-propyl cinnolyn-3-carboxylic acid (1.0 g) in anhydrous ethanol (30 ml), which is stirred and heated at reflux temperature on a steam bath. After 1 hour, the solution was poured into a mixture of ice and water (200 g) and the white precipitate formed was filtered and washed with water. It is recrystallized from benzene and get 4-hydroxy-6-n-propylcinnolyn-3-carboxylate, so pl. 202 ° C.

Similarly, the esters given in the table were obtained from the corresponding starting materials.

SOB.

4 - Oxy-6-n-propyl-cinnolyn-3-carboxylic acid, used as a starting material, was prepared by the following method.

Titanium tetrachloride (1.69 ml) was added to p-n-propylphenylhydrazone p-n-propylphenylhydrazone (2 g) in nitrobenzene (20 ml) to mesoxalyl chloride. The mixture was heated in a water bath for 6 hours, then cooled and diluted with ether (100 ml). Water (100 ml) is added and the mixture is stirred and the mixture is made alkaline with 5N. potassium hydroxide solution. The mixture is filtered, the aqueous layer is separated and washed with ether (2 x 50 ml). Thereafter, the aqueous layer is heated to 80 ° C and acidified with concentrated hydrochloric acid to precipitate a white solid, which after cooling is filtered and washed with water. 4-hydroxy-6-n-propyl-cinnolyn-3-carboxylic acid, recrystallized from ethyl alcohol, has n. 257 ° С (with decomposition).

The following carboxylic acids, used as the raw materials in this example, are obtained in a similar way from the corresponding starting compounds:

6 - ethyl 4-hydroxycinolyn-3-carboxylic acid with mp. 252-254 ° С (with decomposition),

b - n - butyl-4-hydroxypinoln-3-carboxylic acid with m. pl. 252-254 ° С (with decomposition) and

6 - cyclohexyl-4-hydroxycinolyn - 3 carboxylic acid with m. Pl. 255-256 ° С (with decomposition).

The mesoxalylchloride-phenylhydrazone derivatives used as starting materials for the preparation of the indicated carboxylic acids were obtained by methods similar to Example 1.

Example 3. A mixture of 6-ethyl-4-hydroxycinnol-3-carboxylic acid (2.0 g), methanol (50 ml) and boron trifluoride etherate (4.0 ml) is heated at reflux temperature for 2 hours . The clear solution is cooled to room temperature and a crystalline solid is precipitated. This product is filtered and washed with cold methanol to obtain 6-ethyl-4-oxycinnolin-3carboxylate; m.p. 233 ° C.

Methyl-b-butyl-4-hydroxypinoln-3-carboxylate was obtained in a similar way, m. Pl. 188 ° C (recrystallized from a mixture of acetone and cyclohexane).

Example 4. A mixture of 4-hydroxycinnol-Zcarboxylic acid (1.90 g), thionyl chloride (7.0 ml) and dimethylformamide (0.5 ml) is heated at reflux temperature on a steam bath for 1 hour. Excess thionyl chloride is distilled off on the steam bath, the residue is cooled and mixed with c-bzanol (10 ml). The resulting dark solution is heated at reflux on the steam bath for 1 hour and then cooled and poured into water (100 ml). The solution is neutralized by the addition of saturated sodium bicarbonate solution. The resulting solid precipitate is filtered off, washed with water and drained until it is as dry as possible on the filter. After that, it is washed with a small volume of diethyl ether; to remove some co-gritchr; n Kop; ii:; eBoro oils; After crystallization from benzene (with charcoal treatment), n-bzthyl-4-hydroxycinnolip-3-carboxylate is obtained; m.p. 163-165 ° C.

Example 5 Sulfuryl chloride (0.3 ml) was added dropwise to a stirred suspension of 4-hydroxy-6-phenylcinoline-3-carboxylic acid (0.27 g) in anhydrous methanol (20 ml). The mixture is heated at reflux temperature.

on the steam bath for 18 hours. after which it is cooled and filtered. The yellow solid is washed with methanol (5 ml) and crystallized from 50% (volume) aqueous dimethyl sulfoxide (40 ml) to obtain

methyl 4 - hydroxy-4-phenylcinolin-3-carboxylate; m.p. 256-257 ° C (with decomposition).

Example 6. Sulfuryl chloride (0.25 ml) is added dropwise to a suspension of 4 - hydroxy - 6-n-propyl cell - 3-carboxylic

acids (0.32 g) in 2 - ethoxyethanol (10 ml). The mixture is heated overnight in a steam bath, then cooled and poured into an ox (100 ml). The resulting white suspension is stirred and filtered. The solid residue is recrystallized from 50% (v / v) aqueous acetate (30 ml) to creep 2-ethoxyethyl-4-hydroxy-6-n-propyl cinnolin-3-carboxylate, m.p. 246 ° С (with decomposition).

Subject invention

Claims (2)

1. Method of producing esters of cinnolcarboxylic acids of formula I where R denotes an alkoxy group with 1-6 .: 1tomes of carbon, alkoxyalkoxy with 3-6 carbon atoms, phenylalkoxy with 7-10 carbon atoms or phenoxy group; benzene ring A can arbitrarily contain from one to four substituents selected from alkyl with 1-10 carbon atoms, cycloalkyl with 5-7 carbon atoms, alkoxy group with 1-5 carbon atoms, phenylalkyl with 7-10 carbon atoms or phenoxy group, halogen atom or phenyl radicals, which themselves may optionally contain from one to three substituents selected from alkyl with 1-3 carbon atoms, alkoxy groups with 1-3 carbon atoms, nitro group or halogen atom, or their salts, with the exception of methyl to ethyl esters of 4-hydroxypinnolyn-3-carboxylic acid, methyl and ethyl esters of 6-chloro-4-oxycinnol-3-carboxylic acids, and ethyl ether b - methoxy-4-ok9 Sicinnolyn-3-carboxylic acid; characterized in that the compound of formula II soon II N where ring A is as defined above, or the acid anhydride or acid halide of formula II is reacted with a compound of formula III RH, III where R is as defined above, and the desired product is isolated or salified by conventional methods. 2. A method according to claim 1, characterized in that the acid of formula II is reacted with a compound of formula III in the presence of an acid catalyst. Priority featured: 10.16.70: R is an alkoxy group with 1-6 carbon atoms, a phenylalkoxy or phenoxy group; And - benzene ring, which can be arbitrarily substituted from one to four substituents: on the alkyl group with ten 1-5 carbon atoms, alkoxy group with 1-5 carbon atoms, phenylalkyl group with 7-10 carbon atoms, phenoxy group, halogen atoms, phenyl group, which can be arbitrarily replaced by an alkyl group with 1-3 carbon atoms, alkoxy group with 1-3 carbon atoms, halogen atoms. 08.18.71: A - the benzene ring contains a cycloalkyl substituent with 5–7 carbon atoms; R means an alkoxy group with 1-6 carbon atoms, phenylalkoxy or phenoxy group with 7-10 carbon atoms. 09.21.71: R is an alkoxyalkoxy group with 3-6 carbon atoms and A is a benzene ring, which can randomly contain from one to four) substituents: an alkyl group with 1-5 carbon atoms, an alkoxy group with 1-5 carbon atoms, a phenylalkyl group, a phenoxy group with 7-10 carbon atoms, cyc a coalkyl group with 5-7 carbon atoms, halogen atoms or a phenyl group which can be arbitrarily substituted; on alkyl group with 1-3 carbon atoms, alkoxy group with 1-3 carbon atoms halogen atoms or nitro group.