SU297187A1 - - Google Patents

Description

METHOD OF OBTAINING KUMARIN DERIVATIVES

where R is an aliphatic, cycloaliphatic, araliphatic, aromatic amine residue linked through a nitrogen atom or a 5-6 membered nitrogen-containing acyloxy-free heterocycle;

RI is lower alkyl or aryl; R2 is an alkoxy group which may be in the 5,7-, 6,7-or 7,8-positions;

Ra is an alkoxy group; m - numbers 1,2 or 3.

C h) p

(w)

nose

where R and m have the indicated meanings, or its functional derivative in the presence of a binder: its acid means, followed by isolation of the target product by known methods.

Example 1. 36.3 g (0.1 mol) of 3 - (- y-morpholino-p-hydroxypropyl) -4-methyl 7,8-dimethoxycoumarip is dissolved in 200 ml of anhydrous

benzene and 10.1 g (0.1 mol) of triethylamine are added. A solution of 23 g (0.1 mol) of 3,4,5-trimethoxybenzoyl chloride in 100 ml of anhydrous benzene is added dropwise over 30 minutes while stirring at room temperature, and stirred for 2 hours at room temperature. The mixture is then stirred for a further 5 hour under reflux and is sucked off in a hot state from the separated triethylamine hydrochloride.

The filtrate is washed with water, with a 10% aqueous solution of sodium bicarbonate and esh, once with water and dried over hot sodium sulfate. The solvent is then distilled off in vacuum at 50 ° C. The residue, a colorless crystalline powder, is triturated with a small amount of methanol and sucked off. By recrystallization from methanol, 3- 7-morpholino-p- (3,4,5-trimethoxybenzoxy) propyl 4-methyl-7, 8-dimethoxycoumarin is obtained in the form of colorless crystals, mp. 163-165 ° C.

Yield 42 g (75.5% of the theoretical amount).

Similarly to the method described in this example, the following basic mixed coumarin derivatives can be made. General formula (IV)

CIS-CH-CHQ, -R

(W

CRiV.

Example 2. 18.5 g (0.053 mol. Mol.) 3-y-diethylamino-p-hydroxypropyl) -4-methyl-6,7-dimethoxycoumarin is dissolved in 100 ml of anhydrous toluene. After the addition of 5.4 g (0.0535 mol) of triethylamine, a drop of 12.2 g (0.053 jol) of a solution of 3,4,5-trimethoxybenzoyl chloride in 50 ml of anhydrous toluene is added dropwise while stirring at room temperature. Then it is stirred for 2 hours at room temperature and another 5 hours at 100 ° C. After cooling, the reaction mixture is treated as described in Example 1. It is obtained

thus, 3-7-diethylamino-p- (3,4,5-trimethoxybenzoxy) propyl-4-methyl-6,7-dimethoxycoumarin, t.p. 165-167 ° C.

Exit 27 e (88% of the theoretical amount).

Similarly, as described in examples 1 and 2, the following compounds can be prepared. General Formula (V)

ipCH2-CH-CH2-R

I o il

(2)

00

yz) w

Pr i m i r 3. 48.5 g (0.1 mol. Mol.) Of 3-7 M (methylN- (3,4-dimethoxyphenylisopropyl) -mino-hydroxypropyl 1-4 methyl-7,8-dimethoxycoumarin) dissolved in 300 ml of anhydrous benzene and then 10.1 g (0.1 mol) of triethylamine are added. After that, they are added dropwise, stirring for 1 hour at room temperature, 23 g (0.1 mol) of 3.4 , 5-trimethoxybenzoyl chloride, dissolved in 100 ml of anhydrous benzene. Then stirred for 5 hours under reflux and sucked for 5 hours under reflux and sucked in a hot state from the separated tylamine hydrochloride. Then treated according to example 1. Get 3-7-K-methyl-H- (3,4-dimethoxyphenylisopropyl) -amino-p- - 3,4,5-trimethoxybenzoxypropyl-4-methyl-7,8-dimethoxycoumarin hydrochloride in the form of colorless crystals, mp 125 ° C.

eleven

Yield 56 g (78% of theory).

From the above starting materials, the following compounds can be obtained by the method described in Example 3. General Formula (VI)

12

CK2-CH- "l2-f

(21)

MAIN

The invention relates to the field of the preparation of compounds which can be widely used in the pharmaceutical industry.

A method is proposed for obtaining new coumarin shells derived from formula (I)

CHg.-CH-CH2-R

, (Yes) 2

school

(b)

The method consists in the fact that coumarin derivatives of general formula (II)

  CH-CHj- R

, he

oot;

where R - denotes an aliphatic, cycloaliphatic, araliphatic, aromatic amine residue linked through a nitrogen atom or a hydroxyl group containing 5- or 6-membered nitrogen-containing heterocycle, is reacted with alkoxybenzoic acid of the general formula (P1) Example 4. Formula СНзО-V 26 g (0.0655 zhol} of 3 -H-benzylamino-p-hydroxypropyl) -4-methyl-7,8-dimethoxycoumarin are dissolved in 200 ml of anhydrous benzene and 10.1 g (0.1 tol) of triethylamine are added . Then stirring at a room temperature of stirring, a solution of 23 g (0.1 m, ol) of 3, 4, 5-trimetok-sibenzoyl chloride in 80 M of anhydrous benzene is added dropwise and continue to be transferred for another 2 hours at room temperature. The reaction is then heated to a boiling point 45 50 55 60 and stirred for 5 hours under reflux. After cooling, the filtrate is sucked off from the separated triethylamine hydrochloride and the filtrate is concentrated in vacuo. The residue thus obtained was dissolved in ethyl acetate. For further purification, wash the acetic ester solution with water, 10% anhydrous sodium bicarbonate solution, and again with water. After drying over anhydrous sodium sulfate, the solution of ethyl acetate is concentrated in vacuo and the oily residue is stirred with absolute ether. Thus, 3- 7-H-methyl-H-benzylamino-p- (3,4,5-trimethoxybenzoxy) -propyl-4-methyl-7, 8-dimethoxycoumarin is obtained in the form of colorless needles, so pl. 118-120 ° C. Yield 25 g (64.6% of the theoretical amount). 25 g (0.0423 l) of 3-7-N-methyl-N-benzyl-imipo-p- (3,4,5-trimethoxybeisoxy) propyl-4-methyl-7, 8-dimethoxycoumarin is dissolved in an equivalent amount of hydrochloric acid with 3 g of 5% palladium precipitated on coal at 40 ° C and 2 at. of hydrogen. After about 2 hours, the hydrogenation is complete. The mixture is filtered hot from the catalyst, the filtrate is concentrated in vacuo. The residue is then stirred with absolute ether. After some time, 3-y-methylamino- (3- (3,4,5-trimethoxybenzoxy) -propyl-4-methyl-7,8-dimethoxycoumarin-hydrochloride crystallizes out as colorless needles with mp 166-169 ° C . Yield 19 g (83.7% of the theoretical amount). Example 5. 28 g (0.058 mol) of 3- (YN-6eHyloxycarbonyl-N-n-butylamino-p-hydroxy-ynyl) -4-methyl-7,8-dimethoxycoumarin are suspended in 200 ml of anhydrous toluene and 9 g (0.09 mol) of triethylamine are added. Then added dropwise while stirring at room temperature, a solution of -0.8 g (0.09 mol) of 3,4,5-trimethoxybenzoyl chloride in 80 ml of anhydrous The mixture is stirred for 12 hours at 100 ° C and washed after cooling with a 10% aqueous solution of sodium bicarbonate and water. The toluene layer is separated, dried over anhydrous potash, and then dried, dried under vacuum. The oily residue is stirred under heating with abs. ether and filtered from small amounts of insoluble particles. Leave to stand for a while and then 3-y- [M-benzyloxycarbonyl-Nn-butylamino-p- (3,4,5-trimethoxybenzoxy) - propyl-4-methyl-7,8-dimethoxycoumarin as colorless needles - with t. pl. 98-102 ° C. Yield 28 g (71.2% of the theoretical amount), 28 g (0.0414 mol) of 3-y-M-benzyloxycarbonyl-H-n-butylamino. | 3- (3,4,5 .-. Trimethoxybenzoxy) - propyl-4-methyl-7,8-dimethoxycoumarin was added, stirring at room temperature, to 80 g of glacial acetic acid saturated with hydrogen bromide. After the substance is dissolved in the formation of carbon dioxide, it is stirred for another 1 hour at room temperature. Following this, the clear reaction solution is diluted with 5 times the amount of abs. simple ether.

) 2 .8- (-jij)., -6.7- (OCH,)

- 5.7- {OCH,)

,

-N-A-0-CO- / Y-OCH,

Н7 - СН-Г Н2 Ч

UN,

(U

A -CH2-CH2-CHj-CH2-CH2 - After some time, the hydrobromide of 3-7 n-butylamino-3- (3,4,5-trimethoxybenzoxy) propyl-4-methyl-7,8-dimethoxycoumarin is separated. in the form of crystalline powder with m. pl. 90 ° C. Yield 23 g (89% of the theoretical amount). Example 6. 38.75 g (0.1 mol) of 3 - (- N-Methyl-Np-hydroxyethylamino p -sdroxypropyl) -4-methyl-7,8-dimethoxycoumarine hydrochloride are dissolved in 200 L1L of anhydrous chloroform and 30, 3 g (0.3 mol) of triethylamine. In a transparent solution, a solution of 46 g (0.2 mol) of 3,4,5trimethoxybenzoyl chloride in 150 ml of anhydrous chloroform is added dropwise at room temperature with stirring over 1 hour. After completion of the exothermic reaction, stirring is continued for 2 hours at 40-50 ° C. The resulting reaction solution is first washed several times with water, then with 10% aqueous sodium bicarbonate solution and again with water. The solvent is then distilled off in a vacuum, obtained by means of a water-jet pump at 40 ° C, and the residue is dissolved in light yellow oil for further purification in dilute aqueous hydrochloric acid. This solution is extracted with ether and filtered to a clear state. The addition of potash to an alkaline reaction (pH 9) separates the desired diester as a colorless oil. Extracted with acetic ester, the acetic ester solution is washed several times with water and dried over hot sodium sulfate. The solvent is distilled off at 40 ° C in vacuo and the residue, a colorless oil, is dissolved in anhydrous ether. Addition of awj ef of ethereal hydrochloric acid to acidic reaction of the Congo yields hydrochloride 3-; -M-methyl-N-p (3,4,5-trimethoxybenzoxy) -ethylamino- 3- (3,4, 5-trimethoxybenzoxy) - propyl - 4-methyl-7,8 dimethoxycoumarin as colorless crystals with mp. 118 ° C. Output 63 g (81% of the theoretical amount). In a similar way, as described in example 6, it is possible to obtain the following derivatives corresponding to the general formula (VL)

15

Example 7. 47.8 g (0.1 mol) 3 {-Y-4-p (ethoxycarbonyloxy) -ethyl-lipazino 1 -hydroxypropyl} -4-methyl-7.8-dimethoxycoumarin and 10.1 g (0, 1 jol} of triethylamine. Then add dropwise at room temperature while stirring a solution of 23 g (0.1} l) of 3,4,5-trimethoxybenzoyl chloride in 100 zl of anhydrous chloroform for 1 hour. After the exothermic reaction is complete mix esh, e 2 hours at 40-50 ° C and work up as above.You get 3- {v4- p- (ethoxycarbonyloxy) -ethyl-pylerazino (3,4,5-trimethoxybenzoxy) lropyl-4-methyl- 7, 8-dimethoxycoumarin in the form of crystals with mp 88-90 ° C.

Yield 55 g (82% of the theoretical amount). 67.2 g (0.1 mol of 3 {7-4-p- (ethoxycarbonyloxy) -ethyl-piperazino 1 - P- (3,4,5-trimethoxybenzoxy) propyl} -methyl-7,8-dimethoxycoumarin is stirred in for 4 hours at 70–80 ° C in 100 g of 10% aqueous hydrochloric acid. After cooling, the clear solution is made using potash to silk reaction and the separated colorless oil is extracted with acetic ester. After drying, over hot sodium sulfate is concentrated at 40 ° C in vacuo and the residue is a colorless oil, dissolved in anhydrous ether. Addition of hydrochloric acid to the onset of acid Congo reactions are prepared with (p-hydroxyethyl) piperazino dihydrochloride (3,4,5-trimethoxybenzoxy) propyl-4-methyl-7,8-dimethoxycoumarin as colorless crystals with a melting point of 155 ° C.

Yield 45 g (67% of the theoretical amount).

Subject invention

The method of obtaining coumarin derivatives obsh, her formzly (I)

sixteen

“-Oh

where R is an aliphatic, cycloaliphatic, araliphatic, aromatic amine bound via a nitrogen atom, or an acyloxy-free 5 or 6 membered nitrogen-containing heterocycle,

RI is a lower alkyl or aryl group; R2-alkoxy which may be in the 5,7-, 6,7- or 7,8-positions;

Rs is an alkoxy group; t - numbers 1, 2 or 3,

characterized in that coumarin derivatives of general formula (I)

CHO-CH-CHO-R 2 I2

HE

01)

where R denotes an aliphatic, cycloaliphatic, araliphatic, aromatic amine residue linked through a nitrogen atom or a hydroxyl group-free 5- or 6-membered nitrogen-containing heterocycle, is reacted with alkoxybenzoic acid of the general formula (P1)

,

-J

nooo

(YU

ABOUT)

where R and m have the indicated meanings, or its functional derivative in the presence of an acid binding agent, followed by isolation of the target product by known methods.