SU638257A3 - Method of obtaining isoindoline derivatives or their basic or acid salts - Google Patents

Description

in which R n X have the meanings indicated above,

restore the corresponding reducing agents, such as, for example, Zn and CH3COOM, at a temperature of about 60-150 ° C and the compound obtained by the general formula

(F)

where X and R have the specified value,

subjected to saponification with appropriate bases, such as, for example, K2CO3, KOI, etc., or the corresponding acids, such as, for example, co-citric acid sickle, at a temperature of about 75-180 ° C and the target product is isolated or subjected to etherification if RI is hydrogen.

From the above and subsequent succession of the reactions, it follows that if the compounds of the general formula (I), where R) is alkyl, are required, the reaction can be interrupted. Hibernation is reacted when compounds of the general formula (IV) are prepared, where X is a carbalkoxy group.

The esterification of compounds of the general formula (I) in which RI is hydrogen, iridescent to form compounds of general formula (I), in which the RI group, which is not hydrogen, is carried out in accordance with conventional methods, irinated in organic. chemistry So, for example, complex effluxes of a compound of general formula (I) in which RI is hydrogen, with 2- (dimethylamio) ethanol, can be obtained by treating these SOCb compounds with temeregur irimerio 60-90 ° C in the presence of and; n1 without solution) 11te, teG1 and then by the subsequent reaction of the acid chloride obtained using the specified method with 2- (dimethylamiio) ethanol and comic temperature in non-polar solvents such as dioxol, Beisol.

The compound of general formula (I), where Ri is hydrogen, can also be converted into their salts by reacting with inorganic bases, such as KaOI, Ca (OI) 2 n, or organic compounds, such as 2- (dimstilamino ethanol. For example, salts of compounds of the general formula (I) in which RI is hydrogen, which are formed by reacting with 2- (dimethylamio) ethanol, can be obtained by ir (to shia temperature during the process of reaction of these compounds; not 1111 in: c) one solution, containing a stoichiometric amount of 1: a mixture of 2 (dimethplamio) ethanol, followed by lyophilization. Compound (I) compounds in which RI and the groups are

(h},

s

can also be converted into their salts 11) and interactions with organic or inorganic acids.

Irimer 1. A mixture of 14.8 g (0.1 mol) of phthalic anhydride and 19.3 g (0.1 mol) of ethyl-amino (a-methyl) -phenylacetate in 70 ml of glacial acetic acid was heated under reflux 4 h, then cooled to a temperature of about 40 ° C and diluted with 50 ml of water. The thus obtained oily precipitate was acidified by dissolving it in the powder, then cooled to 0 ° C, filtered, and 40 ml of water were washed through, resulting in crystallization from 99.9% EtOH to give

30 (93% yield) K- {4- (a-methyl) -carbethoxymethyl-phenyl} -phthalimide, m.p. 113-114 0. In the same way and as a result of the chemical reaction of phthalic anhydride with the corresponding amio esters

The following compounds were obtained:

N - 4- (carbethoxymethyl) -phenyl - phthalimide, t. Il. 150-152 ° C;

N - {4- (a-ethyl) -carbethoxnmethyl-phenyl} -phthalne, t.nl. 108-109 ° C;

N - {4- (a-yropyl) -carbethoxymethyl-feiyl} -phthalimide, t. Nl. 119-121 ° C;

K - {4- (a-butyl) -carbethoxymethyl-feiyl} -phthalimide, t. Il. 80-82 ° C. Irimer 2. To a solution of 16.1 g (0.05 mol)

N - {4- (a-mcpl) -carbethoxymethyl-phenyl) -phthalimide, suspended in 200 ml of acetic acid, was added while displacing 19.6 g (0.3 mol) of cyclo-papa powder. The mixture was heated under reflux for 4 hours, (|) iltrated, and then the precipitate was poured with ml of acetic acid. The filtrate is viyarina. Cleaned to dryness with iodine, the precipitate was again dissolved in 100 ml of water and neutralized with sodium bicarbonate until the pI, rabbi 7, was reached. The resulting solid and product was filtered, resulting in crystallization from ligroin and 13.9 (yield 90%) 1-oxo-2 {/; - (cc-methyl) -carbethoxymethyl-phenyl} isoindoline, m.p. 99-101 ° C. In the same manner and psycho-use as the source and products of phthalimides obtained according to Example 1, the following compounds were obtained:

1 - oxo-2 - {/ g- (carbethoxmetl) -phenyl} isoindoles, t. Nl. 122-124 ° C;

1 - oxo-2 - {/ g (on-nroipl) - carbethoxymethyl-feiyl} -isoiidoline, t. Nl. 105-106 ° C;

1 - oxo-2 - {/ g- (-butyl) -carbethoxymethyl-phenyl) -psoiidolium, m.p. 106-107 ° C;

Irimer 3. A mixture of 12.36 g (0.04 mol)

1 - oxo-2- {- (a-.methyl) -carbethoxymethyl feiyl) -isoiidoline, 12.36 g of CASO and 230 ml

95% of E1OI in 182 ml of water was heated with

reflux for 8 hours, while achieving complete dissolution. Ethyl alcohol was evaporated in vacuo, the aqueous solution was acidified with 55 ml of 8% hydrochloric acid, the resulting precipitate was filtered, washed with 55 ml of water, resulting in 9.1 g of crystallization from 95% EtOH (yield 81%) 1-oxo-2- {p (a-methyl) -carboxymethyl-phenyl} - isoindoline, so pl. 213-214 ° C.

The following compounds were also prepared:

1 - oxo-2- / g- (carboxymethyl) -phenyl isopidoline, m.p. 208-209 ° C;

1 - oxo-2 - {/ g- (a-ethyl) - carboxymethyl phenyl} -isoindoline, so pl. 180-182 ° C;

1 - oxo-2 - (“- (ss-propyl) -carboxymethyl-phenyl) -isoindoline, m.p. 160-162 ° C;

1 - oKco-2- (n-f (a-butyl) -carboxymethyl phenyl} -isoyl 11doline, mp 145-147 ° С.

PRPMER 4. A mixture of 17.8 g (0.12 mol) of phthalic anhydride and 14.61 g (0.1 mol) of p-amino (a-metl) -phenylacetonitrile in 90 ml of glacial acetic acid was heated with an abrasion cooler for 4 hours while achieving complete dissolution. Then the mixture was cooled and the separated solid product was filtered, washed with water and evaporated, and 22.1 g (yield 80%) of K- {4- (a-methyl) -carbonitrilemethyl-phenyl} -phthalimide were obtained, mp. 213-215 ° C.

In the same way and as a result of the chemical reaction of phthalic anhydride with the corresponding aminonitriles, the following compounds were obtained:

N - {4- (carbopitrilemethyl) -phenyl} -phthalimide;

N - (4- (a-ethyl) -carbonitrilemethyl-phenyl} -phthalimide;

N - {4- (a-propyl) - carbopri, tmethyl phenyl} -phthalimide;

N - {4- (a-butyl) -carbonitrilemethyl-phenyl} -phthalimide.

Example 5. To a suspension of 2.76 g (0.01 mol) of N - {4- (a-methyl) -carbonitrilemethyl phenyl} -phthalimide in 50 ml of glacial acetic acid heated to 70 ° C, 4 g were gradually added. zinc powder. Then the mixture was heated under reflux for 4 hours. The inorganic layer was filtered, the filtrate was cooled and the solid product thus obtained was filtered, treated with water, then 50 ml of 8% NaHCO.3 and sium was filtered. The precipitate was crystallized from 99.9% EtOH, resulting in 1.83 g (yield 70%) of 1 -oxo-2- {p- (a-methyl) -carboiitrylmethyl-phenyl} -isoindoline. m.p. 192-194 ° C. In the same way and using derivatives as derivatives of the starting products, Example 3 was prepared according to a dangerous example. The following compounds were obtained:

1 - oxo-2- “- (carbonitrilemethyl) -phenyl isoindoline;

1 - oxo-2 - {/ g- (cc-ethyl) - carbonitrilemethyl-phenyl} -isoindoline;

1 - oxo-2 - {/; - (i-propyl) -carbopitrimethyl-phenyl} -isoindoline;

1 - oxo-2 - {/ g- (a-butyl) -carbonitrilemethyl-phenyl} -isoindoline.

Example 6. Suspension of 2.62 g (0.01 mol) of 1-oxo-2- (rt- (a-methyl) -carbointrylmethyl-phenyl} -isoindolium in 2.42 ml of concentrated sulfuric acid and 7.4 m, n water was heated under reflux for 16 hours, then added to 100 ml of cold water. The separated solid product was filtered, then treated with 30 m, 8% NaOn. The insoluble precipitate was filtered, and the filtrate was acidified with 30 ml of 8% hydrochloric the acids, the solid product was filtered and the crystal was cleaved from 95% Eton to give 2.39 g (yield 85%) I-oxo-2- {p- (a-methyl) -carboxymethyl-phenyl, 71} -iso-iido , tia, t . p, t, 213-214 C.

The following compounds were also prepared:

1 - oxo-2- “- (carboxymethyl) -phenyl isoindoline, m.p. 208-209 ° С:

1 - oxo-2 - {; g- (a-ethyl) - Kyoboxymethyl phenyl} -isoindoline, t, pl. 180-182 ° C;

1 - oxo-2 - {/ 7- (oc-propyl) - klpbok mpgtil-phenyl} -isopndoline, m.p., 160-162 ° C;

1 - oxo-2 - {/ - (a-butyl) -carbox and fetiline, 1} -isoinlo, 1in, mn, h. 145-147 ° C.

Example 7. A solution of 15.4 g (0.055 mol of 1 - oxo-2 - {/; - (a-methyl) - carbox-simethyl feiyl} -isotp1doline and 6 ml of concentrated sulfuric acid in 180 ml of anhydrous methyl alcohol was heated with a fridge 6 hours , cooled and (1i, chtrova, ti, and washing precipitate, 1 and 100 m, g of 2% NaHCO.i, resulting in a pic, those crystal, pization from methyl alcohol received 15.5 g (yield 96%) 1-oxo -2- {g- (amethyl) -carbomethoxymethyl-phenyl} -isoindoline, etc., 124-126 ° C,

In the same way and as a result of the chemical reaction of the alcohol with the corresponding isoindolins, the following compounds were obtained:

1 - oxo-2- / - (carbomethoxymethyl) -phenyl-isoindolium;

1 - oxo-2 - {/ 7.- (a-these, t) -carbomethoxymethyl-phenyl) -isoindoline;

1 - oxo-2- (7- (a-propyl1 - carbomethoxpmethyl-phenyl} -isoindoline;

1 - oxo-2 - {"- (a-butyl) -carbomethoxymethyl-chienyl} -isoindoline.

Example 8. A solution of 20 g (0.0714 mol) of 1 - oxo-2 - ("- (a-methyl) - carboxymethyl hyenyl} -isoindoline and 120 ml of SOCl. Heat a refrigerator in 3 hours and then distill off the excess SOCIo, followed by the addition of 150 ml of anhydrous benzene to the solution. After evaporation to dryness and treatment with petroleum Ephprom, the solid product was filtered and after crystallization from a mixture of benzene and petroleum ether, 18.15 g (yield 85%) of 1-oxo chlorohydride (a-methyl) -carboxymethyl-phenyl} -isoindoline, etc., 132-134 ° C.

12 g of this acid chloride was further dissolved in 200 ml of anhydrous dioxane, the solution was added along the channels with simultaneous efficient stirring to a solution of 12 ml of 2- (dimethylamino) ethanol in 200 ml of anhydrous dioxane, resulting in a weak exothermic reaction. The mixture was stirred for 3 hours at room temperature, then left to stand overnight. The resulting precipitate was filtered off and the filtrate evaporated in vacuo to give an oily precipitate. This precipitate was dissolved in 150 ml of CHCl3, the chloroform solution was washed with 100 ml of 2% NaHCOs, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. Then the precipitate was extracted with hot hexane and then cooled, resulting in a yield of 11.3 g (yield 80%) of 2- (dimethylamino) -etayl 1-oxo-2- {p- (a-methyl) -carboxymotoyl-phenyl} ether - isoindoline, so pl. 61 -63 ° C.

In the same way, the following compounds were obtained by reacting 2- (dimethylamino) ethanol with the acid chlorides of the corresponding isoindolines:

2- (dimethylamino) ethanol 1-oxo-2- “- (carboxymethyl) -phenyl - isoindo„ tin; ester;

2- (dimethylamino) ethanol 1-oxo-2 - {«- (a-ethyl) -carboxymethyl-phenyl} isoindoline;

2- (dimethylamino) ethanol 1-oxo-2- {p- (a-propyl) -carboxymethyl-phenyl} -isoindoline ester;

2- (dimethylamino) ethanol ester of I-oxo-2- (p- (a-butyl) -carboxymethyl - with |;) enyl} isoindoline.

Example 9. 1 ml of 2- (dimethylamino) ethanol was added to 2.8 g (0.01 mol) of 1-oxo2 - {"- (a-methyl) - carboxymethyl - phenyl} isoindoline suspended in 100 ml of water. Then the solution was lyophilized, resulting in 3.7 g (yield 100%) of 2- (dimethylamino) ethanol salt.

1-oxo-2- {p- (a-methyl) -carboxylmethyl-phenyl} -isoindoline.

In the same way and as a result of the chemical reaction of 2- (dimethylamino) ethanol with the corresponding isoindolines, the following compounds were obtained:

2- (dimethylamino) ethanol salt of 1-oxo2- {«- (a-ethyl) - carboxymethyl-phenyl} isoindoline;

2- (dimethylamino) ethanol salt of 1-oxo2- (and- (a-propyl) -carboxymethyl-phenyl} pzoindoline;

2- (dimethylamino) ethanol salt of 1-oxo2- {rt- (a-butyl) -carboxymethyl-phenyl} isoindoline.

Example 10 To 22.5 g (0.15 mol) of phthalic anhydride was added to 16.5 g (0.1 mol) of a- (4-aminophenyl) propionic acid, dissolved in 200 ml of glacial acetic acid, and then a mixture of bales reflux for 20 h. After cooling to room temperature, the resulting precipitate was washed with glacial acid and then with water. Evaporation to a dry residue under vacuum gave 26.5 g (yield 90%) of N- {4- (a-methyl) -carboxymethyl-phenylethl-phthalimide, m.p. 233-235 ° C. To a solution containing 29.5 g (0.1 mol) of N- (4- (a-methyl) -carboxymethyl-phenyl} -phthalimide in 450 ml of toluene, 125 g of zinc powder was added with stirring and the reaction mixture was heated to reflux. An aqueous solution of 50% sulfuric acid (1.5 mol

sulfuric acid per 1 g-atom of zinc).

The reaction mixture was heated under reflux overnight, the toluene was distilled off using azeotropic distillate with water. After cooling to room temperature, filtering, washing with water and suspension in water, 21 ml of 35 Be sodium hydroxide was added to dissolve the product. After heating to 50 ° fiO ° C, an i-large amount was added

ammonium sulfide and bleaching wood COAL. After filtration, the pH was adjusted to 5-6 by adding xous acid. Cooling to room temperature, heat, drinking, rinsing with water and crista.paly gave 26.3 g (93% yield) of 1-oxo-2fw-f (a-metpl1-k rboc1 and methyl-phenyl} -isoindoline, mp 213 -214 ° C.

USING similar procedures, GOT the following compound:

1 - oxo-2-G / 7- (carboxymethyl) -phenyl pzoipdolip, so pl. 208-209 ° С:

1 - oxo-2- ((a-Etpl) -carboxymethyl Lepil) -isoindoline. m.p. 180-182 ° C; I-oxo-2- (p-1 (a-pro; 1l) -carboxymethylhyenyl | -and: 5Oy1HLf.p. 160-162 ° C;

1 - oxo-2- (l- () -carboxymethyl fenpl-isoipdoline, mp 145-147 ° C.

Subject i.h.

The method of obtaining isoindoline derivatives of general formula

3j / tri-iloOiri (l)

where R is hydrogen or lower Cj-C, RI is hydrogen, lower alkyl Ci-C4 or 60 group of the general formula. ABOUT

TO:

-i (; ir2) "- 2 (

where n is 1 or 2, and each of the radicals R2 and Kz, independently of one another, is hydrogen or lower alkyl Ci-Ci,

or their basic salts, if Ri is hydrogen, or their acidic salts, if Ri is a group

X

(

or cyano and R has the indicated value,

phthalimide formed of the general formula

(F)

phthalic

characterized in

that anhydride of the general formula

ten

in which R and X have the indicated meanings, the compound of the general formula

15

L

jf - // VvtM-IX (SG)

by compound

subjected to the interaction of the general formula HjN-: in which X-carboxy-, carbalko in which X and R have the indicated meanings, or are isolated, or subjected to saponification with the appropriate bases or the corresponding acids and the target product is isolated or subjected to esterification if RI is hydrogen or converted to basic or acidic salts.