SU294330A1 - METHOD OF PREPARING Y-SUBSTITUTED 1,2-DI HYDROCHINO-LINES OR THEIR 5-, 6-OR 7-DERIVATIVES - Google Patents

Description

The invention relates to the preparation of new compounds that can be used in the pharmaceutical industry.

The proposed method for the preparation of N-substituted 1,2-dihydroquinolines or their 5-, 6 or 7-derivatives of the general formula

ICHglnRr

X C-0-P

where RI, R2 and Kz are hydrogen, halogen, trifluoromethyl, lower alkyl-, alkoxy-, thioalkyl-, alkylsulfonyl, hydroxyl-, alkanoyloxy, amino, alkoxycarbonyl orogrunga or a group

Alks

K- (CH,) „Alk

n is an integer from O to 3, X is oxygen or sulfur,

where n is an integer from 1 to 3, Rs and Re is hydrogen, lower alkyl, alkoxy,

halide, trifluoromethyl,

the halide (or thiogaloid) formate is reacted in an organic solvent medium with 1,2-dihydroquinoline or quinoline, followed by treatment of the quinoline salts with an alkali metal borohydride and isolation of the target product by a known method.

Example 1. A. 1,2-Digpdrohinolin.

To a boiling solution of 12 g (157 molly) in 600 ml of anhydrous ether, add a solution of 20 g of quinolp in 100 ml of ether. Within 5 hours, the solution is heated under reflux and settled for 12 hours. Then 10 ml and 5 ml of irp 0 ° C water were added to the mixture. The mixture is stirred. The precipitate is filtered and washed with ether. The combined ether phase is dried over magnesium sulfate and concentrated to vacuo. The resulting solid was dissolved in 25 ml of anhydrous ether and poured into a Klsena flask with a capacity of 50 ml equipped with a Vigre column. The ether is distilled off, the precipitate is distilled. Receive 9 g (45%) of 1,2-dihydroquinoline, t. Kip. PO-115 ° C / 7 mm Hg, which hardened at room temperature. After recrystallization in 10 ml of spun petroleum ether t. Kip. 66-75 ° C, after double recrystallization receive with so pl. 62-66 ° C.

B. 1,2-dihydroquinoline-ethyl carboxylate.

To a solution of 15.13 g of 1,2-dihydroquinolium (115 mmol) B, 40 ml of benzene and 16 ml of triethylamine (115 mmol) are added but cannulated while stirring and cooling to 5 ° C, a solution of 22 ml (230 mmol ) ethyl ester of chlorogolic acid in 40 ml of dry benzene. After stirring for 1 hour at room temperature, the ethylamine hydrochloride is filtered off, the filtrate is taken up with an aqueous solution of hydrochloric acid, and the benzene solution is dried with anhydrous sodium sulfate. The solvent is removed in vacuo and the precipitate is fractionated. From fraction with t. Kip. 118-120 ° C / 0.5 AIM RT. Art. 1,2-dihydroquinoline - M-ethyl carboxylate is produced (B; input 50-76%). This product is distilled 11 |) and 98-100 ° C / 0.04 mm Hg. st ..

Found,%: C 72.57; H 6.55; K 6.62.

CizHisNOs.

Calculated,%: C, 70.92; H 6.44; N 6.89.

The ultraviolet spectrum showed the presence of a conjugated double bond in 233 mmk. (e 27770) in ethanol, with 7/01 m U.C., IR and NMR spectra correspond to the provided structure.

Example 2. 1,2-Dihydroxphenol-K-pzobutyl carboxylate. The reaction was carried out in the same manner as in Example 1. Chlorosulfuric acid ethyl ester for Menin on chlorobolic acid isobutyl esters.

From 13.1 g of 1,2-dihydroquinoline, 10.2 g of triethylamine and 10.8 g of chlorobolic acid isobutyl ester, 10.5 g (45% yield) of 1,2-dihydroquinoline-M-isobutyl carboxylate, t.kip. 115-120 ° C / 0.05 m. M. Art.

Found,%: C 72.53; H 7.34; N 6.07.

Cl4Hl7O2.

Calculated,%: C, 72.70; H 7.41; N.

Example 3. To a solution of 9.1 g (70 millimoles) of 1,2-dihydroquinoline in 55 ml of B 13ol was added 10 ml (75 mmol) of triethylamine. The solution is cooled to 10 ° C after which 10.2 g (70 mmol) of chlorogolic acid p-chloroethyl ester dissolved in 20 ml of benzene is added dropwise to it, and the mixture is stirred and cooled. After settling for five days at room temperature, the reaction mixture is washed with 150 ml of a 10% aqueous solution. The organic phase is decanted and washed again with 150 ml of the above aqueous solution. The organic phase is then separated and dried with sodium sulfate, after which the solvent is removed by distillation in vacuo. The precipitate is distilled twice at 130 ° C / 0.05 mm Hg. Art. 7 g of p-chloroethyl 1,2-digpdro.ing linnogo-N-carboxylate are obtained.

Found,%: C 60.72; H 5.63; N 6.12.

C, 2Hi2NO2Cl.

Calculated,%: C 60.64; H 5.09; N 5.89. A repeated experiment using m pyridine instead of triethylamine gives the same product m. Bale. 120-122 ° C / 0.04 mm Hg. Art.

Example 4. A solution of 9.45 g (101 mmol) of chlorogolic acid methyl ester in 25 ml of benzene is added dropwise to a solution of 101 mmoles of 1,2-dihydroquinoline and 105 mmol of pyridine in 100 ml of benzene. Solution for

15 minutes stirred while cooling, and after that it is defended for 19 hours. The mixture is then shaken with 50 ml of ZMHC1 and the organic phase is separated, and the mixture is washed three times with 50 ml of distilled water to

neutral, dried with sodium sulfate. m and subjected to fractionated distillation in vacuo. Obtain 3.5 g of 1,2-dihydroquinoline-N-carboxylate methyl, so Kip. 86-88 ° C / 0.04 mm Hg. Art.

Found,%: C 67.94; H 6.09; X 7.54. ScNPN.

Calculated,%: C 69.82; H 5.86; X 7.40. Example 5. A solution of 9.6 g (70 millimoles) of chlorogolic acid p-butyl ester in 25 ml of benzene is added dropwise to a cooled stirring solution of 70 mmol 1,2-dihydroquinoline and 75 mmol npridine in 75 ml benzene. The solution is settled at room temperature for 21 hours,

It is washed with 50 ml of 3XHCI. The aqueous phase is decapitated. The organic phase is washed with three portions of 50 ml of water each time until the neutral reaction of the washing waters, dried with sodium sulfate and fractionated in vacuo. Get 4 g of 1,2-dihydroquinoline-N / g-butyl carboxylate, so Kip. 118 - 120 ° C / 0.05 mm Hg. Art.

EXAMPLE 6 48 g of quinoline was added dropwise to 550 ml of a 12.5% solution of diisobutyl aluminum hydride in n-hexane and diethyl ether (in equal parts), under nitrogen at 5 ° C. Quinoline is added to the solution and the red color of the solution disappears. Within 2 hours the solution is maintained at 5 ° C, and then

100 ml of a 20% aqueous solution (by weight) of sodium hydroxide is added to it for 1 hour while stirring at a temperature between 5-10 ° C, under nitrogen. After that, the solution is dried with sodium sulfate, and the solvent

removed in vacuo. 47 g (95%) of crystalline 1,2-dihydroquinoline are obtained.

13.1 g (0.1 mol) of 1,2-dihydroquinoline is dissolved in 30 ml of chloroform (freed from oxygen by passing through it

nitrogen) and cooled to -20 ° C in a mixture of solid carbon dioxide and acetone. 10 ml of triethylamine and 24 g of chlorogolic acid ethyl ester salts were added to the solution. The mixture is heated to room temperature for 1 hour. After that, the mixture is washed with 30, 3NHC1 sludge and three times in 30 ml of water until neutral. It is then dried with sodium sulfate and distilled. Obtain 11 g of 1,2-dihydroquinolin-M-ethyl carboxylate, so Kip. 105-107 ° C / 0.04 mm Hg. Art.

Example 7. 5.3 g of 1,2-dihydroquinoline is subjected to reaction with a solution of 2.5 g of the salt of chlorothionic acid ethyl ester in 50 ml of chloroform, at -10 ° C. Within 5 hours, the mixture is settled at 25 ° C, washed with 50 ml of 3NHC1 and water until neutral wash water. Dry with magnesium sulfate and evaporate. 3.77 g (85%) of 1,2-dihydroquinoline-1H-ethyl thioncarboxylate are obtained, t. Bale. 140-144 ° C / 0.1 mmHg Art. and so on 52-54 ° C.

Example 8. 14.3 g of 7-methylquinoline was added dropwise to 120 liters of a 12% solution of diisobutyl aluminum hydride in a mixture of n-hexane and diethyl ether, taken in equal amounts, under nitrogen. This mixture is incubated for 14 hours at 20 ° C. Then, 100 ml of a 20% aqueous solution of sodium hydroxide was carefully added to it with vigorous stirring and cooling to 5 ° C. The ether layer was separated, dried with magnesium sulfate and evaporated in vacuo. 14.5 g of 1,2-dihydro-7-methylquinoline is obtained, which is dissolved in 100 ml of chloroform and cooled to -20 ° C. To this solution was added 20 m. I salts of ethyl ester of chlorogolic acid. After 30 minutes, 15 ml of triethylamine is added dropwise and cooled. Stand for one day at room temperature and get 14 g of 1,2-dihydro-7-methylquinoline-M-ethyl carboxylate, so Kip. 108-110 ° C / 0.05 mm Hg. Art. Found,%: C 72.19; H 6.81; N 6.53. C.aHisNOa.

Calculated,%: C, 71.85; H 6.96; N 6.45. Example 9. To a solution of 6.5 g (50 mmol) of 1,2-dihydroquinoline in 100 ml of chloroform at -20 ° C was added 17.1 g (100 mmol) of the chlorogolic acid benzyl ester salt. While stirring 30 minutes later, triethylamine 6 ml (50 mmol) was added while cooling. After 24 hours of settling, the organic phase is washed with 50 ml. Dry with magnesium sulfate and evaporate. Get 9 g of 1,2-dihydroquinoline-M-carboxylate benzene, t. Kip. 174-176 ° C / 0.1 mmHg Art. Found,%: C 77.10; H 5.97. CiyHisOsN.

Calculated,%: C, 76.96; H 5.70. Example 10. To 13.1 g (100 mmol) of 1,2-dihydroquinoline and 12 yl (100 mmol) of triethylamine, dissolved at -20 ° C in 100 ml of chloroform, about 150 mmol of isopropyl is added dropwise during stirring and cooling dropwise. chlorotic acid ester. After 60 hours at room temperature, the basic solution is acidified with 100 ml of 3NHC1, after which the acid phase is decanted. The chloroform phase is washed with 100 J / .g of distilled water and then with bicarbonate to pH 8. The organic phase is dried with magnesium sulfate, filtered, evaporated in vacuo, and the residue is subjected

distillation. Obtain 3.5 g of 1,2-dihydrohiyulin-K-isopropyl carboxylate, t. Kip. 82-84 ° C / 0.001 .1LU rt. Art. Re-distillation is carried out at 80-82 ° C / 0.001 mm Hg. Art. Found,%: C 72.32; H 6.95.

С, ЗН ,, -, 02Х.

Calculated,%: C, 71.86; H 6.96. Example 11. To a solution of 13.1 g (100 mmol) of 1,2-dihydroquinoline and 12 and / .g of triethylamine in 100 ml of chloroform at -20 ° C

about 150 mmol of chlorogolic acid p-ethoxyphenyl ester is added dropwise with stirring and cooling. After 65 hours at room temperature, the basic solution is taken up in 100 ml of 3NHC1 and the organic phase is collected by decantation. It is washed with 100 ml of distilled water and then with 100.yl bicarbonate. The residue is distilled. Obtain 15 g of 1,2-dihydroquinolin-K- | 3-ethoxyphenyl carboxylate, t. Kip. 154-158 ° C / 0.005 mm Hg. Art. Found,%: C 77.12; H 6.40. CisH.-OsN.

Calculated,%: C 77.39; H 6.13. Example 12. Technological process

was carried out as in Example 4, with the difference that the 1,2-digndroquinoline used in it was replaced by an equimolecular amount of 1,2-dihydro-6-methylsulfonylquinoline. Get 1,2-dig 1dro-b-methylsulfonylquinolinN-ethyl carboxy.tat.

Example 13. 0.1 mol of 1,2-digdro-7-allyl quinoline is dissolved in 30 ml of chloroform and cooled to -20 ° C. To the solution was added 10 ml of triethylamine and 24 g of chlorotic acid ethyl ester. The mixture is stirred, and it is allowed to stand at room temperature for 16 hours. Moreover, the first hour of the above should be from cold to room temperature. Mixture

washed with 30 ml. ml of hsn1, and then with three portions of water, 30 ml each. The mixture is then dried with sodium sulfate and distilled in vacuo. A 1,2-dihydro-7-allyl quinolin N-ethyl carboxylate is obtained.

Subject invention

The method of obtaining N-substituted 1,2-dihydroquinolines or their 5-, 6- or 7-derivatives of the general formula:

R,

Ri

60

alkoxccaropylamino group

amino, group

L / A.

) M- (CH,) „Alk is a whole number from O to 3, oxygen or sulfur,

carboxy group, alkyl, alkenyl, alkynyl, cycloalkyl with C 3-8, haloalkyl, aralkyl or radical

(CHalr

where n is an integer from 1 to 3, Rs and RB are hydrogen, alkyl, alkoxyl, halo, trifluoromethyl, characterized in that the halogen (or halo) formate is reacted in an orgapic solvent with 1,2-dig 1dr .iiolipom or hipoliiom, with subsequent processing of the formed hiioliiiyevyh salts with alkali metal borohydride and secretion of the target product by the lime method.