SU461494A3 - The method of obtaining coumarin derivatives - Google Patents

Description

(54) METHOD FOR OBTAINING KUMARIN DERIVATIVES

one

A method for producing new coumarin derivatives of the general formula is proposed.

R.O (Z). R4-N-C-NIl-t

where RI, R2, Kz and R4 are the same or different, a hydrogen atom, a straight or branched alkyl group with 1-4 carbon atoms, an unsubstituted or substituted hydroxyl group, a cycloalkyl, aralkyl or aryl group, an unsubstituted or mono- or disubstituted halogen atom , lower alkyl, lower alkoxy, hydroxyl or trifluoromethyl group, or the radicals Ri and R2 or Rs and R4 together with the nitrogen atoms substituted by them form a 3-7-membered heterocyclic ring with 1-3 heteroatoms, unsubstituted, mono- or disubstituted with aryl, unsubstituted or hydroxyl-substituted lower alkyl group, halogen atom, or trifluoromethyl group;

Rs is a hydrogen atom, a lower alkyl group with 1 to 3 carbon atoms or an aryl group preferably with 1 ring system;

Z is a halogen atom or a lower alkyl or alkoxy group with 1 to 3 carbon atoms;

n is an integer O-2;

and - a straight or branched lower alkylene group with 2-5 carbon atoms, unsubstituted or substituted with a hydroxyl group,

or their salts with acids. These compounds have valuable physiological properties.

The method is based on the reaction of the interaction of isocyanates with amines.

The method is that the compound of the general formula

20

25

where R, R2, Rb, U, Z and p have the indicated meanings.

subjected to interaction with the compound of the General formula

t} 3

HN-R,

where Rs and R4 are as defined,

and isolate the desired product or salt it in conventional manner.

The reaction is carried out, for example, by simply heating the components without a solvent or in solvents. The latter use such polar solvents as chloroform, ethylene chloride, chlorobenzene, nitrobenzene, and tak: e dimethylformamide and dimethyl sulfoxide, and inert aromatic hydrocarbons (benzene and toluene).

Getting the original compounds.

4-methyl-3- (2-morpholinoethyl) 2-OXY-2H-1-benzopyran-7-yl isocyanate hydrochloride.

36 g (0.125 mol) of 7-amino-4-methyl-3- (2-morpholinoethyl) -2-oxo-2H-1-benzopyran are stirred in 500 ml of absolute chlorobenzene, cooled to -20 ° C and stirred vigorously. Then, phosgene is passed through the stirred suspension, which liquefies at this temperature. After increasing the volume to approximately 100 ml, the feed is stopped, the mixture is left to stand until it reaches room temperature (approximately 1 hour), then it is slowly heated, and the volatile excess phosgene is cooled and absorbed by ammonia. After one hour of refluxing, the mixture is cooled to room temperature, filtered and the precipitate washed with ether. The compound melts at 231-234 ° C, decomposing, the yield is almost 1007 about the theoretical (44.8 g). The compound is sensitive to moisture, but remains in vacuum for quite some time.

Similarly, you can get:

{4-methyl-3-2- (4-methyl-1-piperazinyl) ethyl -2-oxo-2H-1-benzopyran-7-yl) isocyanate hydrochloride,

4-methyl-3- (2-perhydroazepinoethyl) -2-oxo-2 / -1-benzopyran-7-yl isocyanate hydrochloride,

4-methyl-3 - (2-pyrrolidinoethyl) -2-oxo-2H-1-benzopyran-7-yl isocyanate hydrochloride,

4-methyl-3 - (2-diethylaminoethyl) -2-oxo-2H-1-benzopyran-7-yl isocyanate hydrochloride,

4-methyl-3- (2-methylcyclohexylaminoethyl) -2-oxo-2 // - 1-benzopyran-7-yl isocyanate hydrochloride,

4,8-dimethyl - 3 (2-morpholinoethyl) -2-oxo-2H-1-benzopyran-7-yl isocyanate hydrochloride,

hydrochloride 4-methyl - 3- (2-hydroxy-3-morpholinopropyl) -2-oxo-2Я-1 - benzopyran - 7-yl isocyanate,

4-methyl-3- (2-hydroxy-3-piperidinopropyl) -2-oxo-2Я-1 hydrochloride - benzopyran - 7-yl isocyanate. Example 1. (2-Morpholinoethyl) -4methyl-2-oxo-2Я-1-benzopyran-7 - (3-phenyl-2-methyl-2-propyl) urea.

5.3 g (0.015 mol) of 4-methyl-3 (2-morpholinoethyl) -2-oxo-2H-1-benzopyran-7-yl isocyanate hydrochloride is suspended in 50 ml of absolute chloroform. Within 5 minutes at room temperature, 5.2 g (0.035 mol) 3-phenyl-2-methyl-2-propylamine is added dropwise to the suspension, and the temperature rises to 35 ° C. After a further two-hour stirring, the clear solution is washed twice with 2N. sodium carbonate solution and then twice with water. After that, the chloroform layer is dried over sodium sulfate, evaporated, and the residue is chromatographed

in a solvent chloroform / methanol (95; 5) on silica gel. The compound melts at 222-224 ° C, decomposing, the yield is 5 g (72% of the theoretical).

Found, "/ o: C 70.04; H 7.19; N 9.18.

C27H33N3O4.

Calculated,%: C 69.95; H 7.18; N 9.07. Example 2. (2-Morpholinoethyl) -4-methyl-2-oxo-2 // - 1-benzopyran-7 - yl - 3- (2-phenylethyl) urea.

In a suspension of 5.3 g (0.015 mol) of 4-methyl-3- (2-morpholinoethyl) -2-oxo-2H1-benzopyran-7-yl-isocyanate hydrochloride in 30 ml of absolute chloroform at room temperature, stirring is added drop m

2.05 g (0.017 mol) of 2-phenylethylamine dissolved in 5 ml of absolute chloroform (the temperature rises by about). After stirring for one hour, the suspension is washed with 2N. sodium carbonate solution,

the precipitate is filtered off with suction, then washed with isopropyl ether and purified in a silica gel column with chloroform / methanol (9: 1). The compound melts at 278-28GS, decomposing, the yield is 2.2 g (33.8% of the theoretical). Found,%: C 68.74; H 6.73; N 9.77.

C25H29N3O4.

Calculated,%: C 68.94; H 6.71; W 9.65.

Example 3. N - 3- (2-Mopfolinoethyl) -4 methyl-2-ox-2H-l-benzopyran-7-yl-4-morpholinocarboxamide. To a suspension of 5.3 g (0.015 mol) of 4-methyl-3- (2-morpholinoethyl) -2-oxo-2H1-benzopyran-7-yl-isocyanate hydrochloride in 50 ml of absolute chloroform at room temperature is added dropwise 3 g (0.035 mol) of morpholine (the temperature rises by

). After stirring for two hours, the clear solution is washed with 2N. sodium carbonate solution, then with water, dried over sodium sulfate, evaporated and purified in a column of silica gel with a solvent

chloroform / methanol (9: 1). The compound melts at 269.5-271 ° C, decomposes, the yield is 3.6 g (64% of the theoretical).

Found,%: C 63.05; H 6.84; N 10.41.

CsiHarNaOg.

Calculated,%: C, 62.82; H 6.78; N 10.47.

Similarly, the examples described can be obtained

(3-morpholino-2-hydroxypropyl) - 4 - methyl 2-oxo-2Я-1-benzopyran - - morpholine-carboxamide, so pl. 224-226 ° C;

(3-piperidino-2-hydroxypropyl) - 4-methyl-2-OXO-2Я-1 - benzopyran-7-yl -1 - piperidinocarboxamide, so pl. 203-205 ° C;

(2-pyrrolidinoethyl) -4-methyl-2-oxo2J-1-benzopyran-7-yl -1-pyrrolidinocarboxamide, m.p. 236.5-238.5 ° C;

. (2-perhydroazepinoethyl) -4-methyl-2oxo-2Я-1-benzopyran-7-yl -1-perhydroazepinocarboxamide, so pl. 225 ° C;

L- {3- 2- (4-methylpiperazin-1-yl) ethyl-4methyl-2-oxo-2H-1-benzopyran-7-yl} -4-methyl 1-pyrazinecarboxamide, so pl. 261 ° C;

(2-morpholinoethyl) -4,8 - dimethyl-2-oxo-2Я-1-ben opiran - 7-yl-4-morpholino carboxamide, so pl. 240-241 ° C;

(2-diethylaminoethyl) -4-methyl-2 - oxo 2I-1-benzopyran -, 3 - diethylurea, t. Pl. 190-191 ° C;

l- {3- 2- (N-cyclohexyl-N-methylamino) ethyl-4-methyl-2-oxo-2H-1-benzopyran-7yl} -3-cyclohexyl-3-methyl urea, -t. square 211 ° C (decomposition);

(2-morpholinoethyl) -4-methyl-2-oxo 2Y-1-benzopyran-7-yl-3,3-diethyl urea, t. Pl. 219-220 ° C;

1 (2-morpholinoethyl) -4-methyl-2-oxo2I-1-benzopyran-7-yl-3-gret-butylurea, m.p. 300 ° C (decomposition);

(2-morpholinoethyl) -4-methyl-2-oxo2Y-1-benzopyran-7-yl 3,3-bys- (2-hydroxyethyl) urea, so pl. 187 ° С (decomposition);

(2-morpholinoethyl) - 4 - methyl-2-oxo2J-2 - benzopyran - - phenylurea, so pl. 290 ° C;

(2-morpholinoethyl) -4-methyl-2-oxo2I-1-benzopyran- (2-hydroxyethyl-1-piperazinecarboxamide, mp 210 ° C (decomposition);

(2-morpholinoethyl) - 4-methyl-2 - oxo2I-1-benzopyran - 7-yl - 1-piperidinocarboxamide, so pl. 256 ° C (decomposition);

(2-morpholinoethyl) -4-methyl-2-oxo2Y-1-benzopyran-7-yl-3-cyclohexylurea, m.p. 275 ° C (decomposition);

(2-diethylaminoethyl) -4-methyl-2-oxo2Y-1-benzopyran-7-yl-3-phenylurea, m.p. 265 ° C (decomposition);

(2-morpholinoethyl) - 4,8-dimethyl-2-oxo-1-benzopyran-7-yl - 4- (2-hydroxyethyl) -1-piperazinecarboxamide, so pl. 186-187 ° C;

(2-morpholinoethyl) -4-methyl-2-oxo2I-1-benzopyran-7-urea silt, mp 300 ° C (decomposition);

(2-morpholinoethyl) - 4-methyl-2 - oxo2I-1-benzopyran - 7 - - methyl - 4 - morpholino carboxamide, so pl. 256-257 ° C (splitting);

(2-morpholinoethyl) - 4-methyl-2-oxo2I-1-benzopyran - 7-, 3-diisopropylurea, t. Pl. 215 ° C (decomposition);

(2-morpholinoethyl) -4-methyl-2-oxo2J-1-benzopyran-7-yl-3-greg-butyl-3- (2oxyethyl) urea, so pl. 175-176 ° C (decomposition);

(2-morpholinoethyl) 4,8-dimethyl-2-oxo2I-1-benzopyran - 7-, 3-bis- (2-hydroxyethyl) urea, so pl. 201-202 ° C;

(2-morpholinoethyl) -4-methyl-2-oxo2I-1-benzopyran - (4-methylphenyl) urea, so pl. 295 ° C (decomposition);

(2-morpholinoethyl) -4-methyl-2-oxo2I-1-benzopyran - (4-chlorophenyl) urea, so pl. 290 ° С (decomposition);

(2-morpholinoethyl) -4-methyl-2-oxo2Y-1-benzopyran-7-yl-2-methyl-1-aziridino carboxamide, t. Pl. 200 ° C (decomposition);

(2-morpholinoethyl), -4-methyl-2-oxo2I-1-benzopyran- (4-methoxyphenyl) urea, t. Pl. 280 ° C (decomposition); (2-morpholinoethyl) -4-methyl-2-oxo2Y-1-benzopyran-7-yl-3, 3-dicyclohexylurea, m.p. 235 ° C.

Subject invention

The method of obtaining coumarin derivatives of the general formula

R.O

R4-N-C-NH

where RI, Ra, Rs and R4 are the same or different, the hydrogen atom is a straight or branched alkyl group with 1-4 carbon atoms, unsubstituted or substituted

a hydroxyl group, a cycloalkyl, aralkyl or aryl group, unsubstituted or mono- or disubstituted by a halogen atom, a lower alkyl, lower alkoxy, hydroxyl or trifluoromethyl group, or the radicals Ri and R2 or Ra and R4 together with the nitrogen atoms substituted by them form 3-7 a membered heterocyclic ring with 1–3 heteroatoms, unsubstituted, mono- or disubstituted with aryl, unsubstituted or substituted with hydroxyl lower alkyl group, halogen atom or trifluoromethyl group;

Rs is a hydrogen atom, a lower alkyl group with 1 to 3 carbon atoms or aryl

group preferably with 1 ring system;

Z is a halogen atom or a lower alkyl or alkoxy group with 1 to 3 carbon atoms;

ti is an integer O-2;

and - a straight or branched lower alkylene group with 2-5 carbon atoms, unsubstituted or substituted with a hydroxyl group,

or their salts with acids, distinguished by the fact that the compound of the general formula

I

/J-n-N-.R5

f

RS

in which Ri, R2, Rs, and, Z and n have the indicated meanings,

react with a compound of the general formula

Pda-nc

where RS and R-i have the indicated values, n isolate the target product or translate it into a salt by conventional methods.