SU1066462A3 - Process for preparing 1-substituted-spiro(imidazo-lidine-4,3-indoline)-2,2,5-trione or its salts, racemates or optically active isomers - Google Patents

Abstract

The method of obtaining 1-substituted Spiro L-imidazolidin-4,3-indoline -2,2, 5-trione of the general formula O II 0 tXg. where R is c - C - alkyl, phenyl, naphthyl methyl, or cinamyl, the aromatic rings1} of which, if necessary, carry one or two halogen, or R-benzyl / optionally bearing one, two, or three substituents independently selected from the group, including halogen, trifluoromethyl C-Q-alkyl, Cd-C-alkoxyl, cyto, cyano and hydroxyl; the benzene ring A. bears one substitute, if necessary, selected from the group consisting of halogen, Cd – C alkyl, C – C alkoxy, nitro or hydroxyl, or carries two substituents independently recruited from the group including halogen, alkyl or nctro, with the proviso that when B-methyl, ethyl, J-propyl or unsubstituted benzyl, the benzene ring A is unsubstituted, the sludge and its salts, racemates or optically active isomers, characterized in that idolin-2,3-diso is common Formulas -l-C where R and benzene ring A have the meanings, input tsianidbm reacted with an alkali metal carbonate or carbamates. the amount of ammonium with the selection of the target product in the form of a racemate or ob-. The racemate is processed into the optically active form of the corresponding base to excrete the desired product in the form of an optically active form or in the form of a pharmaceutically acceptable salt .;

Description

This invention relates to a method for producing l-3aMeu; eHHoro cnHpotHivmflB eolidin-4, G-indolin-2, 2, 5-triac of the general formula where R is, alkyl J is phenyl, naphthylmethyl or cinamyl, whose aromatic rings, if necessary, carry one or two , or, in a benzyl, if necessary, bearing one, two or three substituents, independently selected from the group including halogen, trifluoromethyl C., - Gf alkyl, Cd-O-apkoxyl p nitro, cyano and hydroxyl, benzene ring A, if necessary carries one substituent selected from the group consisting of halogen, Sc-Cr-alkyl, Q-Сц-- -alko xyl, nitro and hydroxyl, or bears two substituents independently selected from the group including halogen, C 1 -C 2 -alkyl, or nitro, provided that when R is methyl, ethyl C-propyl or unsubstituted benzyl,. benzene ring A is unsubstituted, go to its salts, racemates, or optically active isomers that have physiological activity. There is a known method of forming an imidazole ring, by reacting ketones with alkali methanoth cyanate in a p & The purpose of the invention is the synthesis of new compounds with valuable properties, suggesting the possibility of using IC in medicine. The goal is achieved by the following method of preparation: an formula of formula 1, based on the well-known reaction, indolin-2,3-dio of the general formula where R and the benzene ring A have the above values reacted with an alkali metal cyanide and ammonium carbonate or carbs with the release of the target product in a racemate or the racemate is optically active. base with the selection of the target product in the form of optically active forgchsh or in the form of a pharmaceutically acceptable SOLRT. In the case where pharmaceutical is required. acceptable salts, react the compound of Formula 1 with the corresponding compound: having a pharmaceutically acceptable cation using a standard procedure. Moreover, when an optically active form of a compound of formula 1 is required, it is possible to react the racemic form of the acetic compound with an optically active compound; form of an acceptable organic base, for example, bruschina, koniyna or 2-pipecoline, followed by (by standard separation of the diistoisomeric mixture of the salts obtained in this way, for example, by fractional crystallization from a suitable solvent, for example Cs-C-alkanol, after which optically ac The active form of this compound can be isolated by treating with an acid according to standard methods, for example, aqueous mineral acid, Tc1 as diluted with salt. The invention is illustrated by examples in which and it is not particularly hooded, evaporation is carried out by rotary evaporation into vacuum, all operations are carried out at room temperature 5, i.e. in the temperature range 18-26 ° C; petroleum ether bale 60-80s) as gasoline 60-80, the other fractions of petroleum ether are referred to as respectively / all compounds 1 are fully characterized based on microanalysis and NMR and IR spectrometry outputs, where given) are indicated for the purpose of illustration and are not necessarily Achieved MtJM o, - Example 1. For 3 hours at 95-100 s boil with a full fridge mixture of 1- (3g-dichlorobenzyl | -indolin-2, 3-dione C12.0 g, ammonium carbonate C36.0 g and potassium cyanide C5.2 g) in 300 ml of methanol and 300: NUI water. The resulting dark solution is slightly cooled and a bleach is added. coal C.3.0 .g). The mixture is then heated to 95-100 ° C. allow sceiwy distilled from methanol. The hot mixture is then filtered, and the residue is washed with hot water. The filtrate and washings are combined, cooled and acidified to pH 2 with concentrated hydrochloric acid. The dark yellow solid is real, detached, collected, npoi & 2HT water, dried in air, fluff, and two times. recrystallized from ethyl acetate / benzyl 60-80 v / v. As a result, it receives 3.3 g of 1-C3, 4-dichlorobenzyl-J-spiro-1-imidazolidine-4, and 3 ind. Rally1-2, 2, 5-trione with m.p. 26927GS. The starting reagent is received by the pup; .-1M way.

Potassium hydroxide ethanol solution (100 ml of 1 M solution) is added to a stirred solution of 14.7 g of indolin-2,3-dione C isatin) in 200 ml of dimethyl sulfoxide. After 10 minutes, a solution of 21.5 g of 3,4-dichlorobenzyl chloride in 10 ml of dimethyl sulfoxide was added. The mixture is stirred for 72 hours and then poured into water (C600 ml). The resulting solid is collected nicknamed water, air dried

and recrystallized from ethyl acetate / gasoline 60-80 (3: 2 v / v 1. The result is 13.8 g of 1-C3, 4-dichlorobenzyl) -indoline-2,3-dione with m.p. 183-184 S.

Examples 2-5. Following the procedure described in Example 1, but using the corresponding indolin-2,3-dione of formula II as starting material, the following compounds will be obtained.

Formula 1.

2-Fluoro-4-bromobenzyl No

Naft-1-ylmethyl

The necessary starting materials of formula 11 are obtained in a manner analogous to that described in example 1 for

 M-propyl

CL3,4-Dichlorobenzyl

298-300 MeCH / E OAc

(.1: 3) 19

268-2701-Pr-CP / Bensin 60-80 (1: 3) 25

synthesis of starting materials using the appropriate isatin and halide of the formula R X. The properties and the yield are given in the table.

6-Chlorine 118-120 Gasoline

57

80-100

EtLOAc:

190-192

40 Gasoline 60-80 (1: 3}

f10664626

Examples 6-33. Following the methodically indolin-2,3-diones of the formula of Example 1, but using i -ra-c, the following compounds are prepared for the starting reagents of Corresponding 1.

2,4-Cl2. -benzyl

Not

253, 4- (5sec benNet

zil

275-277

i-PtOH

270-271 DMF / water

57 No276 26C-SG-benzyl 273,4-sag-benzyl 4-Chloro 264282-CH-benelyl 29 Naft-2-ylmethyl 30 Benzyl 5-Bromo 250314-ce-benzyl 323,4-С22-cin-1 1 33 Phenyl Note. The yield is for recrystallized product.

Ate - purification on a chromatographic column packed with silica gel, 1: 3 (v / v) of ethyl acetate / toluene as an eluting solvent.

The starting materials required indiana-2,3-diones and halo-formulas II should be obtained by a method similar to the radicals of the formula R X. described in example 1 for the properties used to synthesize the original substances used in the table are shown substitute.

C12,4-C (lj-benzylNet

Bhz-NonilNet

CI4-Me-benzyl

VgCinamil

Wg -Pentyl

Table continuation

T D 2482502822322571 AcOH EtOAc 266 EtOAc 250 Petrol 252 Petrol 60-80 Et CPC 252 Petrol 60-80 283 tOAc 233 Petrol 259 Ditto

There is no 194-196 E-tOAc. 55

Note. The yield is for recrystallized product.

a-1 is made as a waxy solid, purified by flash chromatography on silica, using ethyl acetate / toluene 1: 1 v / v as the elastant.

WITH,

1-phenylindolin-2,3-dione for examples. Examples 34-40. Following measure 33) is obtained in the form of a solid procedure of Example 1 and used as a material with m.p. 138-139 ° C (overlapping of the initial corresponding 1-installation from propan-2-ol) from the outlet - substituted indolin-2,3-diony by 56% by Ford (method of the patent CU1Amuli P will receive the following compounds 3509149). a formula of the formula 1. 383,4-SkeO) -benzyl 5-CU-7 -Ke 393,4-Dichlorobenzyl 402-Ftschr-4-bromo-se-7-Me benzyl

Note. The yield is indicated for the recrystallized product. The required starting compounds — indoline-2,3-dione with a halo of formula II are obtained by a method analogous to a formula in X. described in Example 1 for i for i. The resulting intermediate results of the preparation of the starting compounds (fop compounds have the following peculiarities li, t .e. by reaction of compliance.

4-megabenzyl

Vg

Methyl

Table continuation

156-158 i-PrOH 52

5-SG

170-172 i PfOH 60

5-CI 285-287 EtOH / 2-MeO273-175 -EtOH E-lCac / 247-249 / Gasoline 60-80

3Bgn-Hexyl

4CI3,4-Ce-benzyl

CI3,4- {Meo) j benzyl

CI 3,4-Ctij-6eHsil

CI 2-F-4-Br-6eHZIL P.R. and M e h a and u e. The yield is given for Example 41. A filtered solution of 3.76 g of 1-C3, 4-dichlorobenzyl) -spiro: imidazolidin-4,3-indolyl 1-2,2,5-trione in 20 ml of water is evaporated in 20 ml of water, the contents of 0.40 g caustic soda, the remaining traces of water are removed by azeotropic distillation with toluene. As a result, the corresponding monosodium salt is obtained with a quantitative yield in the form of an amorphous hygroscopic solid, with satisfactory microanalysis data. Example 42. dI-1- (3,4-Dichloro-benzyl) -spiro-Cimidgslidin-4H-indolin3, 2,5-trione (4.4 g) is added to 61, 5 ml of a 0.18 M solution of hydroxide IN, N, H-trimethyl-C1-phenylethyl-ammonium. The mixture is heated to dissolve and then the precipitate is evaporated, dissolved in warm propan-2-ape CI. The resulting solution is cooled to OC within 48 hours. The crystalline solid that is formed is collected by filtration and washed with cold propan-2-ol (.5 ml), then petroleum ether 4060 (20 ml), and recrystallized twice from propan-2-ol. Instructed. “Α-diastereoisomeric salt of 1-S, N hydroxide, c-trimethyl-C-phenylethyl) - ammonium and at. -1-C3 / 4-dichlorobenzyl) -shyroSimidazolidin-4, 3-indolinZ-2,2, 5-trione 0-, 6 g), so pl. 148-150 C. Dili + 32.8 (s, 1.4; MeOH).

Continuation of the table

5-CI86-88i-PfOH 49

4,5-CIt, 185-187 EtOAc /

/ Gasoline 60-8071

5-CI162-164 i-РгОН /

/ DMF 33

5-CI-7-ME 191-194 MeON / -MeO-EtOH 41

5-CI-7-iWE 179-182 MeCK / 2-MeOEtOH, 43 recrystallized product The salt (J., 6 t) is dissolved in water with ClC ml and methanol C3 ml 1 and the solution is acidified with concentrated qolic acid C1 ml). The precipitated solid is collected, washed with water and recrystallized from ethanol to give dL-1- (3, 4-dichlorobenzyl) -spiro-imidazapidin-4, 3-indoline, -2, 2., 5-trione, m.p. . 199-200 C, tijLl +41 Cc, 1.6 MeCh). Quaternary hydroxide stock solution is obtained by passing aqueous 1: K, N, N-trimethyl-11-phenylethyl3-ammonium iodide solution (27.8 g) through an Amberlite IRA 401 anion-exchange resin, 200 gU, re-turns, oxygen in hydroxy oxide form CAraberlite is a trademark). Other individual enantiomers of optically quaternary ammonium hydroxides, Hanpt (Mep N hydroxide, and, M-trimethyl- (1-methyl-2-hydroxy-2-phenylethyl O-ammonium, can also be used to cleave the racemic forms of the compounds of the formula G. Examples 43 -55, Using a procedure similar to that described in Example 1, but proceeding from the approach of this indoline-2, 3-dione of formula D, the compounds of formula 1 are obtained in 1570% yields,

brombeneyl

44 3,4-Dichloro. benzyl

45 3,4-Dichlorobeneyl

46 3,4-Dichlorobenzyl

47 3,4-Dichloro benzyl.

48 2-Fluoro-4-bromo-5-nitrobenzyl

49 4-Nitrobenzyl

50 3,4-Dichlorocinamil

514-Hydroxybenzyl

523,4-Dichlorobenzyl

533.4-Dichlorobenzide 543.5-Dichlorobenzyl 553.4-Dichlorobenzene

Missing 290-242

Aqueous dimethylformamide

286-287 Ethyl acetate / gasoline

4-Chlorine 60-80

5,6-Dimethyl 262-263 Ethyl acetate / gasoline

60-80

232-233 Ethyl acetate / gasoline

7-Ethyl 60-80

5-Nitro 249-251 Ethyl acetate / gasoline

60-80

5-Nitro 180-181 Isopropanol / Gasoline

60-80

5-Bromo-7-nitro 254-246 Ethyl acetate / gasoline

60-80

5-chloro

295-297 Aqueous dimethylformamcd

285-286

Methanol 244-245

Ethyl acetate / gasoline 80-100

5,6-Dichloro 255-256

Ethyl acetate / gasoline 60-80 No 5-Hydrochloride 237-238 Toluene 296-298 Ethyl acetate / gasoline 60-80

The original indolin-2,3-diones of formula 11 can be obtained analogously to example 1, but starting from.

suitable 1-unsubstituted in3, 5-dichloro-4-bromobenzyl

3, 4-Dichloro-benzyl

3,4-Dichlorobenzyl

3,4-Dichlorobenzyl

3,4-Dichlorocinamil

3,4-Dichlorobenzyl

3,4-Dichlorobenzyl

3,5-Dichlorobenzyl. 1- C4-Hydroxybenzyl) -indolin-2, 3-dione, necessary as a starting material for example 51, can be obtained as follows. This nol solution of potassium hydroxide (C16.6 g in 400 ml) was added to a stirred solution of 43.6 g of indolin2, 3-dione Sisatin) in dimethyl sulfoxide (400 ML). After 10 minutes, a solution of 4-acetoxybenzyl bromide (76.3 g3 in dimethyl sulfoxide (.40 ml) was added. The mixture was stirred for 72 hours and then poured onto ice with water (about 1000 ml). The gum-like product initially formed slowly crystallized. The resulting solid - recrystallized from methanol C500 ml), which gives 1- (4-acetoxybenzyl) -indolin-2,3-dione in the form of a solid, mp 1591 bs. This solid, together with the additional material obtained from the mother liquor, chromatograph on C500 rt silica using toluene, with containing an increasing amount of ethyl acetate BV as eluent (up to 25 v / v%). The aluate fractions collected using eluent containing 20–25 v / v% ethyl acetate are combined and evaporated to give 1- (4-hydroxybenzylCH-indolium-, 3-dione in the form of a copper-melt solid (t. square

Valleys-2, 3-dione and gagugenida formula K X.

The characteristic starting materials for a 1k formula of P are as follows.

24 -243 Methanol

180-182Isopropanol

218-220 Ethyl acetate

124-126 Gasoline 60-80

194-196 Ethyl acetate

170-171TOLUOL

197-200 Ethyl acetate / gasoline 60-80

192-193 Ethanol 28-35 C) after recrystallization from a mixture of toluene and ethyl acetate. It should be borne in mind that the acetoxy group is hydrolyzed to the desired hydroxyl group during chromatography on silica. The ability to inhibit aldehyde enzyme reductase can be established by the following standard laboratory tests. So, in rats, diabetes was evidenced by evidence that glucosuria was strong). streptozotocin. Animals then for 5 days. the compound was administered once a day, after which they were killed and the lens and sciatic nerves were removed. After the standard processing procedure, the residual content of sorbitol is determined in each tissue by gas-liquid chromatography, first converted into polytrimethylsilyl derivatives. The suppression of aldose reductase in vivo is estimated by comparing the residual sorbitol content in the tissues of the diabetic group of rats administered the drug with those diabetic rats that did not receive the drug and with healthy K-ysamms that did not receive the drug. In accordance with another variant of a modified test procedure for rats that have diabetes with streptozocin, daily

Claims (1)

The method of obtaining 1-knitted ^ spiro (imidazolidin-4,3-indoline] -2,2, 5-trion of the general formula where R '- C ₄ - - alkyl, phenyl, naphthylmethyl or cinnamyl, aromatic rings of which, if necessary bear one or two halogens, or R * -benzyl, optionally bearing one, two or three substituents independently selected from the group consisting of halogen, trifluoromethyl C _A -C ^ - '-alkyl, Cx-Cc-apoxyl, nitro, cyano and hydroxyl; benzene ring A, if necessary, carries one substituent selected from the group consisting of halogen, C _d -C ^ -alkyl, Sc-Stsalkoksil, nitro and hydroxyl, or carries two substituents independently selected from the group consisting of halogen, Cd-C ^ alkyl or nitro, provided that when R-methyl, ethyl, H-propyl or unsubstituted benzyl, benzene ring A is unsubstituted, sludge and its salts, racemates or optically active isomers, characterized in that the indoline-2,3-dione of the general formula wherein R 'and the benzene ring A have the indicated meanings, are reacted with alkali metal cyanide and carbonate or carbam-. the ammonium volume with the selection of the target product in the form of a racemate or vol. They work on the racemate with an optically active form of the corresponding one based on the isolation of the target product in the form of an optically active form or in the form of a pharmaceutically acceptable salt.