DE1695275C - Process for the preparation of 3-carbalkoxy-4-hydroxy-quinoline derivatives - Google Patents

Description

OH

COOH

(D

IO

(Π)

N = CH-CH (COOR ₂ ),

with a phosphorus oxyhalide, optionally in the presence of a solvent or diluent, heated and then an optionally obtained 4-halo-quinoline derivative under hydrolyzed under acidic or basic conditions.

The subject of patent 1695 231 are 3-carbalkoxy-4-hydroxyquinoline derivatives the general formula

COOR,

(I)

wherein R ₁ denotes an alkyl group with 12 to 14 carbon atoms or a benzyl group optionally substituted by 1 or chlorine atoms, R ₂ denotes a methyl or ethyl group and R ₃ denotes a hydrogen atom or an alkyl group with 1 to 6 carbon atoms or an alkoxy group with 1 to 4 carbon atoms.

According to the patent 1 G95 231 the connections of the general formula I prepared by either in a known manner

a) a compound of the general formula

(H) N = CH-CI 1 (COOR ₂ ) ;,

(III)

wherein R _{1 is} an alkyl group with 12 to 14 carbon atoms or a benzyl group optionally substituted by 1 or 2 chlorine atoms, R _{2 is} a methyl or ethyl group and R _{3 is} a hydrogen atom or an alkyl group with 1 to 6 carbon atoms or an alkoxy group with 1 to 4 Carbon atoms means, according to patent 1Λ95 231, characterized in that an anil of the general form)

or a halide of such an acid is reacted with an alcohol of the general formula R _: OH.

A further process for the preparation of the compounds of the general formula I has now been carried out found, which consists in that one anil of the general formula

R, Ο — k \ J — N = CH - CH (COOR ₂ ),

heated or

with a phosphorus oxyhalide, optionally: n

Presence of a solvent or diluent! ,, heated and then optionally obtained 4-halo-quinoline derivative hydrolyzed under acidic or basic conditions.

A suitable phosphorus oxyhalide is, for example, phosphorus chloride.

As a diluent or solvent, for. B. toluene in question. The product of the reaction of the Arus with a phosphorus oxyhalide is either depending on the ratio of anil to phosphorus oxyhalide a 4-hydroxy-quinoline derivative or a 4-halo-quinoline derivative. Will be approximately equal molars If proportions of anil and phosphorus oxyhalide are used, the 4-hydroxy-quinoline derivative is obtained. But if the reaction is carried out with the phosphorus oxyhalide in excess by, for. B. 2 to 10 moles of phosphorus oxyhalide are used per mole of anil, then the 4-halo-quinoline equivalent becomes obtained, which is then subsequently hydrolyzed to the corresponding 4-hydroxy-quinoline derivative.

The hydrolysis can e.g. B. with a mixture of acetic acid and sodium acelate or with a diluted one Sodium hydroxide solution or with dilute hydrochloric acid. Will be expedient the hydrolysis also in the presence of a diluent or solvent, e.g. B. xylene. Ethanol or methanol, carried out and accelerated or brought to a conclusion by supplying heat.

The hydrolysis of the intermediate 4-haloquinoline can be carried out after isolation of the intermediate be performed. The crude product obtained by evaporating the excess phosphorus oxyhalide is obtained, but can also be directly subjected to hydrolysis. In the latter case, the addition of a special hydrolyzing agent is necessary not absolutely necessary because the crude 4-halo-quinoline usually has enough hydrogen halide contains to effect hydrolysis. As a rule, heating the raw material is sufficient 4-halo-quinolines in a solvent, ιπ ·> ι the Cause hydrolysis.

If R, is an alkyl radical having 12 to 14 carbon atoms, this can, for. B. the n-dodecyl or n-telradecyl radical. Furthermore, R ₁ can be the benzyl.

2-chlorobenzyl, 4-chlorobenzyl or 2,4-dichlorobenzyl radical being.

Examples of R ₃ are methyl, ethyl, n-butoxy, butyl, isobutyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or isobutoxy radicals

The invention is illustrated by the following examples

example 1

A mixture of 4.2 parts of 3-BenzyIoxy-4-n-prop- ^! ° oxyanilinomethylene malonic acid diethyl ester and 34 parts of phosphorus oxychloride are heated ^{to 100 ° C. for 2.5 hours.} The excess phosphorus oxychloride is evaporated and a mixture of 8.6 parts of xylene, 5.3 parts of glacial acetic acid and 5.6 parts of molten sodium acetate is added to the residue. The resulting mixture is refluxed at 122 to 130 ° C. for 4.25 hours and then cooled. Then 22.5 parts of water are added, whereupon the mixture is shaken. The solid product is filtered off, washed with xylene and then with water, ^{dried at 100 °} C. and then recrystallized from dimethylformamide. This gives 3-carbethoxy-4-hydroxy-6-n-propoxy-7-benzylo-y-quinoline; Mp 277-280 ° C; Yield 87%.

Example 2

A mixture of 2.8 parts of 3-benzyloxy-4-n-bulylanilinomethylene malonic acid - Dimethyl and 10 parts of phosphorus oxychloride is heated to 100 C for 2 hours. Then the excess phosphorus oxychloride evaporated, and the residue is a mixture of 10 parts of xylene, 5 parts of glacial acetic acid and'35 5 parts of anhydrous sodium acetate were added. The mixture is refluxed for 4 hours and then cooled. Then 20 parts of water are added, and the resulting mixture is shaken. The solid product is filtered off, washed with xylene and then from dimethylformamide recrystallized This gives 3-carbomethoxy-4-hydroxy-6-η-butyl-7-benzyloxy-quinoline; M.p. 287 to 288 "C; yield 70%.

45

Example 3

A mixture of 4.2 parts of S-benzyloxy ^ -n-propoxyanilinomethylene malonic acid Diethyl ester and 34 parts of phosphorus oxychloride are heated to 100 ° C. for 2.5 hours. The excess phosphorus oxychloride is evaporated, and the residue is a mixture of 20 parts of absolute ethanol and 0.1 part concentrated hydrochloric acid added. The mixture is refluxed for 6 hours. The The reaction mixture is cooled and poured onto ice. The precipitated solid matter is filtered off, washed with water, dried and recrystallized from dimethylformamide. This gives 3-carbethoxy ^ -hydiOxy-fvn-propoxy ^ -benzvloxy-quino - (, 0 !in; M.p. 280 C: yield 80%.

The procedure described is repeated with the difference that 0.1 part of water is used instead of 0.1 part of concentrated hydrochloric acid. The same compound is obtained; M.p. 279 to 281 ° C. ₍ , ₅

The procedures given are repeated with the difference that instead of S-benzyloxy ^ -n-propoxyanilinomethylene malonic acid diethyl ester another anil is used. This way, in 60 to 80% yield obtained:

3-carbomethoxy-4-hydroxy-6-n-propyl-

7- (4'-chlorobenzyloxy) -quinoline, mp 295 ° C,
S-carbomethoxy- ^ hydroxy-on-propyl-

7- (2 ', 4'-dichlorobenzyloxy) -quinoline, F. 299 ³ C,
3-carbomethoxy-4-hydroxy-7-benzyloχy-

quinoline, m.p. 273 ° C,
3-carbomethoxy-4-hydΓoxy-6-n-propyl-

7-n-dodecyloxy-quinoline, m.p. 256 ⁰ C,
3-carbethoxy-4-hydroxy-6-isobutoxy-

7-benzyloxy-quinoline, m.p. 287 ° C and
3-carbomethoxy-4-hydroxy-6-isobutoxy-

7-benzyloxy-quinoline, F. 290 ⁰ C.

Example 4

A mixture of 4.2 parts of 3-benzyIoxy-4-n-propoxyanilinomethylene malonic acid diethyl ester and 34 parts of phosphorus oxychloride is heated to 100 ° C. for 2.5 hours. The excess phosphorus oxychloride is evaporated and the residue is poured onto ice. The resulting mixture is made alkaline with concentrated ammonium hydroxide solution, and the solid product is filtered off, washed with water, recrystallized in vacuum dried and crystallized from petroleum ether (b.p. 60 to 8O ⁰ C.) is thus obtained. 3 - carbethoxy - 4 - chloro - 6 - η - propoxy - 7 - benzyloxyquinoline; F. 119-120 ⁰ C. There are 4 parts of this chlorine compound is added to a mixture of 8.6 parts of xylene, 5.3 parts of glacial acetic acid and 5.6 parts of molten sodium acetate The mixture is 4.25. heated hours under reflux at 122-130 ⁰ C and then cooled. then, 22.5 parts of water are added and the resulting mixture is shaken. the solid product is filtered, washed with xylene and then with water washed, dried at 100 ° C. and recrystallized from dimethylformamide. This gives S-carbethoxy ^ -hydroxy-6 - η - propoxy - 7 - benzyloxy - quinoline; M.p. 277 to 280 ^° C; Overall yield 53%.

Example 5

A mixture of 50 parts of 3-benzyloxy-4-n-butyl-anilinomethylmalonic acid dimethyl ester, 95 parts of phosphorus oxychloride and 80 parts of dry toluene is refluxed for 6 hours. The toluene and excess phosphorus oxychloride are then evaporated and 180 parts of methanol are added to the residue. The mixture is refluxed for 24 hours and then brought to 0 ° C. The thereby precipitated solid material is filtered off, washed with methanol and then dried at 6O ⁰ C. This gives S-carbomethoxy ^ -hydroxy-6-n-butyl-7-benzylo \ y-quinoline; M.p. 287 to 288 ° C; Yield 80%.

Example 6

A mixture of 4 parts of 3-benzyloxy-4-n-butylanilinomethylene malonic acid dimethyl ester and 20 parts of phosphorus oxychloride is refluxed for 4 hours. The excess phosphorus oxychloride is evaporated, and the residue is treated with 30 parts of methanol and 2 parts of a 2N sodium hydroxide solution4 Heated under reflux for hours. The mixture is then cooled and filtered, whereupon the solid matter is recrystallized from dimethylformamide. So get

one S-carbomethoxy ^ -hydroxy-o-n-butyl ^ -benzyloxy-quinoline; M.p. 287 to 288 ° C; Yield 67%.

Example 7

A mixture of 5.0 parts of ß-benzyloxy ^ -n-propoxyanilinomethylene malonic acid - Diethyl ester and 1.79 parts of phosphorus oxychloride is 1.25 hours heated to 100 ° C. The reaction mixture is diluted with 25 parts of benzene and poured onto 50 parts of ice pour. After the ice and the benzene become liquid the mixture is neutralized with a 30% sodium hydroxide solution.

The three phase system of benzene, water and solid is filtered and the solid is washed with benzene and hot ethanol. The solid substance is ^{dried at 100 °} C. and recrystallized from dimethylformamide. This gives 3-carbethoxy-4-hydroxy-6-n-propoxy-7-benzyloxy-quinoline; M.p. 280 ^° C; Yield 27%.

Claims (1)

Claim: Process for the preparation of 3-carbalkoxy-4 - hydroxy - quinoline derivatives of the general formula OH b) an acid of the general formula