SU299063A1 - - Google Patents

Description

METHOD FOR OBTAINING CUMARIN DERIVATIVES The invention relates to the field of producing compounds that can be used as pharmaceuticals. A method is proposed for the distribution of coumarin derivatives of the general formula N-A-O-CO where RI is hydrogen, a low molecular weight alkyl group, preferably containing 1-4 carbon atoms, or aryl, for example, phenyl carbon; Kg -; alko "S1Igruppa 6,7- or 7,8-: positiNII, -containing 1-4 carbon atoms; Rs is an alkoxy group containing 1-4 carbon atoms; m - numbers 1, 2 or 3; AI - unbranched or branched alkylene residue containing 2-3 carbon atoms; hydrogen, hydroxy group or residue corresponding to the coumaria derivatives of formula A, -N N-Ag-OH in, where X is hydrogen or hydroxy group, is reacted with alkoxybenzoic acid of formula (R RQOC-i i the carbon atoms of the ring can be substituted 1 -3 alkoxygrutines, or with its functional derivative, namely halogen nhydride acid, a1 example bromoanhydride, chlorine anhydride in the presence of an acid binding agent, as well as an indifferent organic solvent npiH which can be within the range komiatpoy temperature and the "as used Eapen emogo in this case the solvent followed prvvrascheniem resulting compound into a salt in a conventional manner so forth:. isoed Ineni n obtained with known products release

MILKING.

Example 1. 37.6 g (0.1 mol) ((5oxyethyl) py): perazino-1-ethyl-4-methyl-7,8-dimethoxycoumarin is suspended in 200 ml of anhydrous benzene, "10.1 g (0.1 mol) of triethylamine. A solution of 23 g (0.1 mol) of 3, 4, 5-trimethoxybenzoyl chloride in 100 ml of anhydrous benzene at room temperature and stirred for 4-5 hours at room temperature is stirred for 30 minutes at a bath with a stirrer. . After that, it is stirred for 2 hours under reflux and sucked off in a hot state from the isolated hydrochloric triethylamine. The filtrate is washed with water, a b / o-pym aqueous solution of sodium bicarbonate and lm, e times with water and then dried over anhydrous sodium sulfate. Then, the solvent is distilled off at a 50 ° C iH vacuum pump and at a jet pump at a temperature of 50 ° C iH dissolve the residue — light yellow, a viscous oil — with a small amount of anhydrous uksuonoethyl ether. After acidification of ethereal hydrochloric acid before acidic reaction in Congo, 3-, 8-4- (| b-3, 4, 5 -trimethoxy Oibenzo COethyl) piperazino-1-ethyl-4-methyl-7, 8-dimethoxycoumarin in colorless crystals with t. dec. 239-240 ° C.

Output 53 g (82Vo from theoretical).

Used as a “similar product, 3- / 5-4- (; 8-o: K Oet1Il) -piperazino-1-ethyl-4-methyl-7, 3-dimethoxycoumarin can be obtained as follows:

a) 13 g (0.055 lyul) 3- (| -oxyethyl) -4-methyl-7, 8-dioxy "umarnna (. obtained as described in Chem abstr. 54, 24690g (1960) method), 40 ml of glacial acetic acid acids and 36 ml of 48 / o-hrO1HM hydrochloric acid are stirred for 5 hours at 110-115 ° C. After cooling, the reaction mixture is poured into a fivefold amount of water and O1 precipitated precipitate is sucked off. The wet further reaction product can be recrystallized from glacial acetic acid. So get 14 g (85Vo from theoretical) 3 - (- bromoethyl) -4-: methyl-7, 8-dihydroxycumaran with so pl. 190 ° C.

Similarly, the following products were obtained: 3 - (;; 3-b romethyl) -4-n-propyl7, 8-dichoquicmarnn with m. Il. 175-177 ° C; 3 - (/ 3bromoethyl) -4-fevil-7, 8-dioxycoumarin with so pl. 211-213 ° C;

i6) 15 g (0.05 l {oly) 3 - (- bromethyl) -4-methyl7, 8-dioquoicoumarin are dissolved in 100 ml of dioxane and 25 g dimethyl sulfate is added. By passing nitrogen gas, 7 g of sodium hydroxide in 20 ml of water are then added dropwise with stirring and at 35-40 ° G ipacTBCp. At 35-40 ° C stir the reaction

the mixture until complete disappearance of the alkaline reaction. After the further addition of 25 g of dimethyl sulfate, a solution of 7 g of sodium hydroxide in 20 liters of water is again distilled. After the reaction is complete, the reaction mixture is concentrated in vacuo and diluted with water. The recovered reaction product is taken up in ethyl acetate and the ethyl acetate layer is washed with diluted sodium hydroxide. Dry a layer of ethyl acetate and concentrate it dry iB. 3 - (/ 3-5-methyl ethyl) -4-methyl-7, 8-dimethoxycoumarin is obtained in colorless crystals with m. Il. 147-149 ° C. Output 13 g (79.3 "/ s

from theoretical).

Example 2. 40.6 g (0.1 mol) of (o-hydroxyethyl) piperazino-1-oxypropyl-4-methyl-7, 8-dimethoxycoumarin are dissolved in 350 ml of anhydrous chloroform and to this is added

10.1 g (0.1 mol) of triethylamine. With stirring, a drop of JM 23 g (0.1 mol) of 3, 4, 5-trimethoxybenzoyl chloride, dissolved in 100 ml of anhydrous chloroform, is then added over 1 hour. After extinction of the exothermic reaction is stirred for another 2 hours at 40-50 ° C. After cooling, water is added, the chloroform phase is separated and washed again with water, 5Vo-Hb -M paiCTBopOM sodium bicarbonate and another

once water. After drying the chlorofor: ma solution over calcined sodium sulfate, the solvent is distilled off in vacuum at 50 ° C. The residue is dissolved in dilute hydrochloric acid with water and, for the purpose of purification, the aqueous is extracted

hydrochloric acid solution with ethyl acetate. The aqueous hydrochloric acid solution is brought to a basic reaction using potash (pP-9) and the reaction product extracted with ethyl acetate and extracted as oil. A solution of acetic ethylether is dried over calcined sodium sulfate, freed from solvent in a vacuum, and the residue is dissolved. Example: but in 100 ml of anhydrous methanol. By adding methanol hydrochloric

the acids are obtained in the following way: 3-f7 -4- (P-3, 4, 5 -grimethoxybenzoxyethyl) dipper hydrochloride 31 II –io; G - -axiro-iyl) -4-methyl-7, 8-d1Imethoxycoumarin in colorless crystals with m. 231-233 ° C (after recrystallization from methanol-water in a ratio of 20: 1).

Yield 59 g (87 / o from the theoretical). The required, as a starting product, 3- t-1- (-oxyethyl) -piperazino-1 - -aiiopropyl) -4methyl-7, 8-dioxycoumarin (obtained as follows:

28.4 g (0.1 mol) of 3-chloro / 3-hydroxypropyl-4-methyl-7, 8-diaxycoumarin (obtained by condensation of a-acetyl-T-chloromethyl-butyrolactone with pyrogallol as described in English patent 1-044.608) are dissolved when heated in 200 ml of dioxane. After cooling to approximately 40 ° C, 40 g of dimethyl sulfate is added and, while stirring, while adding, 42 g of potash in a drop of 80 ml are added dropwise.

the mixture is stirred at a temperature of 40 ° C until; until the sample of the addition of dilute sodium lye shows more yellow color, which will be in about 2-3 hours.

When diluted with water, the reaction product is released in the form of colorless needles. For the purpose of cleaning, dissolve the suction raw product in chloroform, wash the solution with diluted iron and dry it. After concentration and solution of chloroform, 3- T-chloro-oxy1-propyl-4-methyl-7,8-dimethok | SI is obtained (kuma1ri-n in the form of colorless needles with m. (Pl. 142-144 ° С.

Yield 27 g 86.5% of theory.

Similarly, receive; 3-t-chloro / 5-hydroxypro; drank -4-n-pr01pil-7, 8-di. Methoxycoumarin st. square 136-137 °, 3-t-chloro- / 3-oxI1Propyl1-4-phenyl-7, 8-dimethoxyqumarmar.in with mp. 142 °; 3- 7-chloro-0 XSI Pro D saw 4-methyl-7, 8-di-1 etxica, marin with t. Pl. 136-138 ° €. 31.2 g (0.1 mol) of 3-t-chloro- (3-axi-1nrOpyl-4-.methyl-7.8 dime. Hydroxy.1 arin and 13 g of K- / 3-hydroxyethyl pi-1-perezine dissolved in 150 ml of chlorobenzene and stir after adding 11 g of anhydrous soda for 7 hours at a temperature of 120 ° C. After cooling, the filtrate is filtered off with suction of the isolated salt and the filtrate is concentrated under vacuum. The crude product, crystallized after concentration, is stirred for further cleaning with 100 ml of Uxon-ethyl ether, sucked off and kept in vacuum. Get 3-t-4 - (/ -hydroxyethyl) -pitrase1No - -hydroxypronyl -4-methyl-7,8-dimethoxycuma with so pl. 142-145 ° C. The output of 31.3 g (77% of theoretical)

Example 3. 40.6 g (0.1 mol) of 3- {t-4 - (, y-hydroxyethyl) -1piperazino-H - / 3-oxIropyl-4-meth1yl-7,8-dimethoxycoumarin solution 350 ml of anhydrous chloroform are added, and 20.2 g (02 mol) of triethylamine are added. Within 2 hours, then, but dropwise, with stirring, 46 g (0.2 mol) of 3,4,5-trimethomethoxy benzoylchloride, ida, dissolved in 200 ml of anhydrous chloroform is added. The internal temperature rises at the same time shriblizitelio to 50 ° C. After the exothermic reaction decays, they are further stirred for 2 hours at 40–50 ° C and then processed as described in Example 2.

The diester dihydrochloride of the above general structure is obtained in colorless crystals with m. 158 ° C (recrystallized from methanol). Yield 70 g (82% of theoretical).

The above described diester is also obtained when, by the addition of triethylamine, the monoester obtained in Example 2 in chloroform with 3,4,5-trimethoxybenzoyl chloride is prepared for the exchange reaction.

In a round and within 30 minutes, add a drop of stirring, a solution of 23 e (0.1 mol) of 3.4, 5-trimethoxybenzoylchloride: ida in 100 ml of anhydrous benzene and mix for 4-5

hour of room temperature. After another 2 hours under reflux and sucked off in a hot state from the isolated triethylamine hydrochloride. The filtrate is washed with water, with a 5% aqueous solution of sodium bicarbonate and esh, once with water and dried over anhydrous sodium sulfate. The solvent is then distilled off in the resulting | With a water jet vacuum pump at a temperature of 50 ° C, and the residue (light yellow, viscous malo) is dissolved in dilute (aqueous) hydrochloric acid. For purification, extract the hydrochloric (aqueous) solution with ethyl acetate. The potassium carbonate is brought to a clear, aqueous phase prior to the silk reaction and extracted again with ethyl acetate. The ethyl acetate solution thus obtained is washed more times with water, dried over anhydrous sodium sulphate / m, dried to a volume of about 50 ml and brought to a residue.

pure hydrochloric acid to acidic reaction of congo. After recrystallization from anhydrous methanol, isolated 3- -4: - (- 3, 4, 5-trimethoxybenzoxyethyl) iylerazino G-ethyl-4-methyl-6, 7-dimethoxy dihydrochloride ..

KumarIna has m. 224 ° C.

Output 47 g (73% of theoretical)

The 3 / 5-4-) / 3-hydroxyethyl) -i1-operazino-H-ethyl-4-methyl-6, 7-di.methoxy-ul-arin used as starting material can be obtained as follows:

a) 13 g (0.05 mol) of 3- -oxyethyl-4-methyl6, 7-dihydroxycoumarin (obtained by condensation of Xybenzene 1,2,4-grtsetsets Xybenzene with a-acetylbutyrolactone as described in Chem. Abstr. 54, 24690g (1960) method), 40 g of ice-acetic acid and 36 ml of 48% hydrobromic acid are stirred for 5 hours at 110-115 ° C. After cooling

poured the reaction mixture into five times the amount of water and the precipitated precipitate is sucked off. Wet further reaction product can be: Perekrnstaliso: to withdraw from glacial acetic acid. 12 g (73% of the theoretical) of 3- ((3-bromoethyl-4-methyl-6,7-dihydraxncoumarin with so nl. 262 ° C) are obtained. The following products are obtained in a similar way: 3- Rbromoethyl -4 - -nrapil-6, 7-dioxycoumarin with tons of 250-252 ° С, 3- / -bromoethyl-4-phenyl-6,7-dioxycumari and with tons of 255 ° С.

b) 15 g (0.05 mol) of 3-; 5-bromoethyl-4-methyl-6, 7-dioxycoumarin are dissolved in 100 ml of dioxane and 25 g of dimethyl sulfate is added to this. Passing nitrogen gas, then add 1PO drops of stirring and at a temperature of 35-40 ° C a solution of 7 g of caustic soda in 20 ml of aoda. At 35-40 ° C, the reaction mixture is stirred until the alkaline reaction completely disappears. After further lrnbavle