Derivatives of quinoline and method of production thereof

 

(57) Abstract:

Usage: as an intermediate product upon receipt of melacine is a valuable pharmaceutical product. The inventive method of obtaining derivatives of quinoline f-crystals 1 interaction halogenated quinoline derivative f crystals of 3-picoline-N-oxide f-ly 4. The radicals R1X have the meanings given in the description text. The structure of the compounds f-l 1, 3, 4 (see drawing). 1 S. and 2 C.p. f-crystals.

The invention relates to organic synthesis and relates to new quinoline derivatives and the way they are received.

The new compounds according to the invention represent an important intermediate compound for obtaining a pharmaceutically active compounds. In particular, the new compounds are valuable intermediate substances for Erythro-alpha-2-piperidyl-2,8-bis-(trifter - methyl)-quinoline-4-methanol hydrochloride (oflocin). This last active component can be successfully used in pharmaceutically active compounds against malaria.

Known methods for producing melacine have several disadvantages, such as the stage of replacement metal hydrogen directly attached to a carbon atom, Il is testuya the quinoline-4-carboxylic acid), and derivatives of pyridine road and they are hard to reach.

These shortcomings could be successfully eliminated through the application of intermediate compounds quinoline according to the invention.

Thus, the object of the invention are new quinoline derivatives of General formula I

where R1means hydrogen or a group of formula II:

(II) according to the invention compounds of General formula I are obtained by introducing into the reaction derived Alojamientos quinoline General formula III

(III) where X denotes chlorine or bromine, with picolinamides formula IV

in the presence of tert-alkylate of an alkali metal, preferably of potassium tert-butylate.

The use of a suitable condensing agent or an excess of 2-methylpyridine-N-oxide, depending on the solvent and/or the application of the diluted reaction mixture, practically only get monogenoidea derived.

According to the invention can preferably act by introducing into the reaction halogencontaining derivative of General formula III with 2-methylpyridine-N-oxide in the presence of trebuchet sodium, and as the reaction environment of the use of tertiary alcohols or inertiae, dimethyl sulfoxide, preferably toluene or tetrahydrofuran.

The new compounds according to the invention can be isolated from the reaction mixture as illustrated in the following examples. If the connection should be turned into oximeter rearrangement, then the selection of the reaction mixture is not required.

P R I m e R 1.12,73 g of trebuchet potassium and 6.20 g of 2-methylpyridine-N-oxide and 50 ml of tetrahydrofuran are mixed and to the mixture is added 3 g of 2,8-bis(trifluoromethyl)-4-chlorhydrin at 60aboutC. the Mixture is allowed to cool to room temperature and added dropwise to 5 ml of glacial acetic acid at water cooling, and the precipitated mineral salt is filtered and washed with 2 x 20 ml simple ether. The organic layer is evaporated to dryness and the residual 9,31 g of the product mixed with a mixture (1:1) ice and methanol, it is filtered, washed with water and dried. Get of 3.42 g (N-hydroxy-2-pyridyl)-2,8-bis(trifluoromethyl)-quinoline-4-methane. So pl. 156-158aboutC. Analytically pure sample is recrystallized twice from ethanol, so pl. 162-162,5aboutC.

P R I m m e R 2. 16 g of potassium dissolved in hot tertbutanol and received trebuchet potassium suspended in 350 ml of toluene. To the suspension is added at 45about2 is nom cooling, add 125 ml of 10% hydrochloric acid, the aqueous layer was separated and extracted with toluene. The organic layer is dried, lighten active charcoal and evaporated to 150 g under reduced pressure. The mixture is cooled and the precipitated crystalline product is filtered. Get 20,12 g (N-hydroxy-2-pyridyl)-2,8-bis(trifluoromethyl)-quinoline-4-methane. So pl. 157-158aboutC.

P R I m e R 3. To 100 ml of 25% aqueous solution of trapenciere potassium in toluene added according to example 1, 6 g of 2-methylpyridine-N-oxide and 3,44 g of 2,8-bis(trifluoromethyl)-4-brainline. Get 3.57 g (N-hydroxy - 2-pyridyl)-2,8-bis(trifluoromethyl)-quinoline-4-methane. So pl. 155-157aboutC.

P R I m e R 4. To the solution prepared from 3,21 g of metallic potassium and 80 ml of anhydrous tertbutanol add 4.4 g of 2-methyl-pyridine-N-oxide, the mixture is heated to 70aboutWith and add to 4.2 g of 2,8-bis(trifluoromethyl)-4-chlorhydrin. When the reaction is completed adjust the pH to 6 by addition of a solution of concentrated hydrochloric acid, the mixture is stirred for 10 min at 25aboutWith the precipitated substance is filtered and treated with 10 ml of tertbutanol. The mixture is concentrated by suction, dissolved in 100 ml of water and the insoluble part is filtered off and dried. Get to 1.14 g of the product, so pl. 264-265aboutC. After recrystallization from methanol: trifluoromethyl)-4-quinoline)-(N-CA - C-2-pyridyl)-methane. Of uterine alkaline solution of water tertbutanol tertbutanol removed by distillation and the residue is diluted with 100 ml of water, extracted with 3 x 50 ml of chloroform, dried on sodium sulfate and evaporated. After recrystallization of the residue gain of 3.46 g (N-hydroxy-2-pyridyl)-2,8-bis(trifluoromethyl)- quinoline-4-methane, so pl. 159-161aboutC.

P R I m e R 5. At 10aboutWith 350 ml of trebuchet potassium mixed with 2250 ml of hexane and add 100 g of 2-methylpyridine-N-oxide. At this temperature, the mixture is stirred for 1 h, then add 100 g of 2,8-bis(trifluoromethyl)-4-chlorhydrin dropwise dissolved in 200 ml of hexane, and after 6 h stirring at a temperature below 20aboutThe mixture is neutralized with acetic acid. After 90 min the precipitated substance is filtered off, washed with hexane, dried, mixed with 1000 ml of water and the insoluble crude product is filtered, washed with water and dried. Get 102,5 g (N-hydroxy-2-pyridyl)-2,8-bis(tri - vermeil)-quinoline-4-methane, so pl. 152-154aboutC. the content of the active component according D 83,2%

P R I m e R 6. To the mixture 2250 ml of toluene and 250 g of trebuchet potassium with a temperature of 0-5aboutTo add 70 g of freshly distilled 2-methyl-pyridine-N-oxide.

After stirring for 10 min of the reaction mixture is neutralized glacial acetic acid and extracted with water. The residual toluene solution fined, filtered, evaporated and cooled. The precipitated crystalline product is filtered, cover a certain amount of toluene and dried. Get to 89.9 g (N-hydroxy-2-pyridyl)-2,8-bis(trifluoromethyl)-hee - nolin-4-methane, so pl. 157-159aboutC.

The product has a purity of 95.6% of under D.

P R I m e R 7. 125.0 g of trebuchet potassium dissolved in 2250 ml of absolute tetragidrofurana, the mixture is cooled to 0-5aboutFrom and after the addition of 50.0 g of 2-methylpyridine-N-oxide, 100 g of 2,8-bis(trifluoromethyl)-4-chlorhydrin dissolved in 150 ml of tetrahydrofuran, is added dropwise. The solution is neutralized with acetic acid at a temperature below 20aboutWith precipitated salt is filtered and washed with tetrahydrofuran. A solution of tetrahydrofuran is evaporated to 1/10 of the volume and the precipitated product is filtered, washed with water and dried. Get 95,6 g (N-hydroxy-2-pyridyl)-2,8-bis(trifluoromethyl)-quinoline-4-methane, so pl. 159-161aboutC.

The purity of the product according D96,3%

Below are examples of obtaining Erythro-2-2-piperidin-2,6-bis(trifluoromethyl)-quinoline-4-methanol-hydrochlori - Yes (melacine) with the use of new quinoline derivatives according to the invention.

P R I m e R 8. 0,78 ml acetylchloride cobaltichloride at 0aboutC. After four days of aging at room temperature, the mixture was poured on ice, neutralized with solid potassium carbonate, the two layers are separated and the aqueous layer was extracted with 3 x 40 ml dichloromethane. Connected the organic layer is dried over sodium sulfate and evaporated, 3.80 g of residual oil is crystallized from hexane. Get to 2.55 g of 2-pyridyl-2,8-bis(trifluoromethyl)-quinoline-4-IU - canaliculata, and after recrystallization from isopropanol or hexane, the product melts at 104-106aboutC.

P R I m e R 9. 1.54 g of benzoyl chloride is added dropwise to the solution in 3,70 g (N-hydroxy-2-pyridyl)-2,8-bis(trifluoromethyl)- 4-kinalimutan in 50 ml of dichloromethane at 0aboutC. Further processing such as that described in example 1, but the rest of the dichloromethane extract is boiled with 230 ml of hexane and allowed to cool to room temperature, and the precipitated crystalline substance is recrystallized from of 1.62 g of methanol. Obtain 1.4 g of 2-pyridyl-2,8-bis(trifluoromethyl)-quinoline-4-metanovel - soata. So pl. 139-140aboutC.

P R I m e R 10. 20 g (N-hydroxy-2-pyridyl)-2,8-bis(trifluoromethyl)-quinoline-4-methane mixed with 250 ml of 1,2-dichloroethane. With external cooling at 25aboutWith dropwise added to 6.5 ml of ethylchloride, that was followed by 8 ml trevali under reduced pressure. The residue was recrystallized from isopropanol. Received 20.6 g ethyl-2-pyridyl-2,8-bis(trifluoromethyl)-quinoline-4-methanol)-carbonate. Yield: 86.2 per cent so pl. 128-130aboutC.

P R I m e R 11. 6 ml triperoxonane acid diluted with 40 ml of toluene and, at room temperature this mixture is added dropwise to and 3.72 g (N-hydroxy-2-pyridyl)-2,8-bis(trifluoromethyl)-quinoline-4-methane in 50 ml of toluene at room temperature. The mixture was allowed to stand for 1 day, put it in ice water and neutralized with solid sodium bicarbonate, and the two layers were separated. The organic layer was dried over sodium sulfate, evaporated to 15 ml, cooled and the precipitated product was filtered and dried. Received 2.70 g-2-pyridyl-2,8-bis(trifluoromethyl)-quinoline-4-methanol, so pl. 133-135aboutC.

P R I m e R 12. 20 g (N-hydroxy-2-pyridyl)-2,8-bis(trifluoromethyl)-quinoline-4-methane are dissolved in 30aboutWith in 25 ml of acetonitrile and add 15 ml of anhydride triperoxonane acid. After 1 hour was added dropwise 5 ml of water, the solution is evaporated at low temperature to 34 g and was led from isopropanol. Received 16,56 g-2-pyridyl-2,8-bis(trifluoromethyl)-quinoline-4-metadataformat, so pl. 133-135aboutC.

P R I m e p 13. The reaction is carried out according to example 5 in 250 malali 8.6 g of potassium carbonate, dissolved in 10 ml of water, the two layers were separated and the organic layer was osvetleni charcoal, evaporated to about 1/5 and cooled.

The precipitated product is filtered and recrystallized from isopropanol. Get 12,63 g-2-pyridyl-2,8-bis(trifluoromethyl)-quinoline-4-methanol, melting at 138-140aboutC.

P R I m e R 14. Ethyl-(-2-pyridyl-2,8-bis(trifluoromethyl)-quinoline-4-methanol)-CT - Banat obtained according to example 3, boiled 2.2 g (30 ml) of methanol in the presence of 2.8 g of potassium carbonate for 6 hours the Mixture is cooled to room temperature, the organic salt is filtered and the filtrate acidified with glacial acetic acid (pH 6) and cool. The precipitated product was separated as described above. Was obtained 1.4 g of 2-pyridyl-2,8-bis(trifluoromethyl)-quinoline-4-IU - canola (76%), so pl. 138-140aboutC.

P R I m e R 15. 2 g ( -hydroxy-2-pyridyl)-2,8-bis(trifluoromethyl)-quinoline-4-methane stirred for 1.5 h at 50-55aboutWith in 20 ml of propionic acid chloride acid. The reaction mixture is evaporated at moderate temperatures up to 70aboutWith under reduced pressure and the residue was poured on ice, extracted with chloroform and evaporated the residue is crystallized or recrystallized from hexane. Obtain 1.27 g-2-pyridyl-2,8-bis(trifluoromethyl)-hin the 7,22 dd, 6; the shift of the proton of pyridine: 8,55 d3, 6; 7,65, d3, 4; 7,55 dm, 3; 7,24 d3, 5; other: 7,65 with, Metin; 2,60 q, methylene; 1,22 methyl t.

P R I m e R 16. It is possible to carry out the process similar to example 8, but using 20 ml of acid chloride of acid oil. Get 1,72 g-2-pyridyl-2,8-bis(trifluoromethyl)-quinoline-4-metanilpotent, so pl. 68-71aboutC.

P R I m e R 17. 10 ml of di(2,8-bis(trifluoromethyl)4-quinoline)-(-hydroxy-2-pyridyl)-meta - dissolved in 90 ml of acetic anhydride and the mixture is stirred for 2 h at 60aboutC. It is evaporated under reduced pressure, the residue was poured on ice and neutralized with potassium carbonate and extracted with chloroform. The organic layer is dried, evaporated and the residue crystallized from a mixture of chloroform and hexane. Yield 6.3 g (79,1%). Received, di(2,8-bis) of(trifluoromethyl)-4-quinoline)-pyridine-2-methanol-acetate melts at 228-230aboutC.

P R I m e R 18. 1 g, di(2,8-bis(trifluoromethyl)-4-quinoline)-pyridine-2-methanolic - Etat dissolved in 10 ml of anhydrous methanol and to the solution was added at room temperature in a stream of nitrogen, 0.1 ml of a 5 molar methanol-sodium methylate. Mixture is allowed to stand overnight and neutralized glacial acetic acid is evaporated in vacuum and the residue is crystallized from a mixture of hexane and chlorine is iridin-2-methanol. Output: 78,9% so pl. 200-202aboutC.

P R I m e R 19. 1.4 g of 2-pyridyl-2,8-bis(trifluoromethyl)-quinoline-4-methanolate - Tata refluxed for 3 h in 20 ml of 95% ethanol in the presence of 20 ml of 36% hydrochloric acid. The mixture of enlightening in a hot state with activated charcoal, cooled and added to a suspension of 0.9 g of 10% aqueous catalyst Pt/C (Idrich), pre-hydrated with 80 ml of 95% ethanol. The mixture is vigorously stirred in a hydrogen atmosphere at normal pressure for 6 hours (flow rate of hydrogen 240 ml). The catalyst was filtered under reduced pressure and 1.24 g of residue will recrystallized from acetonitrile. Obtain 0.96 g of Erythro - a -(2-piperidyl)-2,8-bis(tricorner)-quinoline-4-IU - manageronline, so pl. 263-264aboutC.

P R I m e R 20. 1.0 g of 2-pyridyl-2,8-bis(trifluoromethyl)-quinoline-4-methanol is added to a suspension of 0.9 g of a 5% catalyst Pt/C, pre-hydrated in 100 ml of 95% ethanol and 2 ml 36,0% hydrochloric acid. The hydration is carried out as described in example 12, and the product isolated. After recrystallization obtain 1.0 g of Erythro--2-piperidyl-2,8-bis(trifluoromethyl)-quinoline-4-meta - nonacetylated. Yield: 90.7% are so pl. 211-212aboutC.

aboutC.

1. Derivatives of quinoline General formula

< / BR>
where R1hydrogen or a group of the formula

< / BR>
2. The method of obtaining quinoline derivatives of General formula

< / BR>
where R1hydrogen or a group of the formula

< / BR>
characterized in that interact halogenated quinoline derivative of General formula

< / BR>
where X is chlorine or bromine,

in the presence of tert-alkylate alkali metal-picoline-N-oxide of the formula

< / BR>
3. The method according to p. 2, wherein interact specified halogenated quinoline derivative of General formula III, where X has the value-picoline-N-oxide in the presence of potassium tert-butylate.

4. The method according to p. 3, characterized in that used as the reaction medium tertiary alcohols, inert solvents, such as aromatic hydrocarbons, cyclic and acyclic

 

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O__N< / BR>
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IN - NR4or CH2< / BR>
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n=1 or 2

IN - NR4or CH2< / BR>
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2 cl, 3 ex

FIELD: chemistry of metalloorganic compounds, medicine, oncology.

SUBSTANCE: invention relates to derivatives of platinum tetrachloride and to a method for their preparing also. Invention proposes compounds of the formula PtCl4 x 2 Li wherein Li represents N-(2-nitroxyethyl)nicotinamide or N-(2-nitroxyethyl)isonicotinamide, or nicotine hydroxamic acid, or isonicotine hydroxamic acid. Also, invention proposes a method for preparing these compounds that involves interaction of pyridine carboxylic acid nitroxyethylamides or hydroxamic acids, or their hydrochlorides with potassium hexachloroplatinate followed by isolation of the end product. Invention provides synthesis of the unknown early chelate platinum compounds that are physiologically active substances and can be used in medicinal practice instead cisplatin as effective anti-metastatic medicinal agents with low toxicity.

EFFECT: improved preparing method, enhanced and valuable medicinal properties of compounds.

2 cl, 3 ex

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