SU707521A3 - Method of preparing new di- or tetrahydrobenz/f/isoindolines, or their isomers, or racemic mixtures of these optical isomers, or their salts - Google Patents

Claims (5)

The reaction is preferably carried out at the boiling point of the reaction mixture. The present invention is illustrated by examples. The N-alkylation reaction is carried out in solvents such as formic acid. The separation of the possible racemic compounds of the formula I into their optical isomers is carried out according to known methods, in particular through the fractional crystallization of salts of these racemic compounds using 4 optically active acids. Example (for RS, 4 SR, 9aSR) -bchlor-4- (p-chlorophenyl) - (For) 4.9 9a-tetrahydro-2-methylbenz (f isoindoles Mixture of 1.5 g (For RS, .4SR , 9aSR) -b-chloro-4- (p-chlorophenyl) -3a, 4,9,9ag-tetrahydrobene isoindoline, 10 ml of 100% formic acid and 10 m of 40% -HGro formaldehyde aqueous solution are heated under nitrogen to boil for 2 hours under reflux. The mixture is evaporated, the residue is taken up in water, the solution is alkalized with a concentrated solution of sodium hydroxide and extracted with methylene chloride. The dried extracts are mixed with ether and mixed with using the Hyflo system and evaporated, and the title compound is obtained as a residue; t. 13 (after crystallization from ether). In analogy to Example 1, the following compounds are obtained from the corresponding starting compounds: (, 4SR, 9aSR) Za, 4,9,9a-tet rahydro-2-isopropyl-4-phenylbranz f yerindolin; mp. Hydromalealeinate 150153 ° С; L.. (For RS, 4SR, 9aSR) Za, 4 , 9,9a-tetrahydro-2,6-dimethyl-4- (p-tolylbenz f isoindoline; t. square bis- (base-naphthalene-1,5-disulfonate 195-198 ° C (Over RS, 4SR, 9aSR) Over, 4,9,9a-tetra hydro-2,6-dimethyl-4-phenylbenz f isoindoline; t Bis- (base) -naphthalene-1,5-disulfonate 280-283С; (For RS, 4SR, 9aSR) For, 4,9,9a-tetrahydro-2,7-dimethyl-4-phenylbenz f isoindoline; mp. bis- (base) -naphthalene-1, 5-disulfonate A 244-248 C; (Over RS, 4SR, 9aSR) For, 4,9,9a-tet rahydro-2, b-dimethyl- 4-phenylbenz (f isoindoline, mp. Bis- (base) -naphthalene-1, 1,5-disulfonate 183-187C (Over RS, 4SR, 9aSR) For, 4,9,9a-tetrahydro-2, 7-dimethyl-4-phenylbenz f. Isoindoline, mp: bis- (base) -naph talin-1,5-di-sulphonate 204-207 ° С; (Over RS, 4SR, 9aSR) Za, 4,9,9a -t etrahydro-2-methyl-4-phenylbenz f isoindoline; mp., bis- (base) naphthal -1,5 disulfonate. 297-303С; hydrochloride- (ZA, RS, 4SR, 9aSR) Za, 4.9 , 9a-tetrahydro-2-methyl-4-phenylbenz f isoindoline, mp 207-209 ° C (ethyl ether), (3a.RS, 4SR, 9aSR) -7-chloro-4- (m-chlorophenyl ) - (Per) 4,9,9a-tetrahydro-2-methylbenz If isoindoline; mp., Bis- (base) -naphthalene-1,5-disulfonate 244-248С; (Over RS, 4SR, 9aSR) -6-hlop-Za, 4.9, fa-tetrahydro-2-methyl-4-phenylbenz tf 1 and eoindoline; m.p. hydrochloride 231233 ° C; (9aRS, 4SR, 9,9a) -dihydro-2-methyl-4-phenylbenz f isoindoline; m.p. hydromaleicate 158-1b2 ° C (decomposition); (Over RS, 4SR, 9aSR) -2-ethyl-b-chloropa, 4.9, 9a-tetrahydro-4-phenylbenz f isoindoline; m.p. hydrochloride 198-200 C; (For RS, 4SR, 9aSR) -2-n-butyl-b-hlop-Za, 4,9,9a-tetrahydrr-4-phenylbenzene (f isoindoline, mp. Fumarate 164165 C; (For RS, 4SR, 9aSR ) -6-chlorop-2-espropyl-3a, 4.9.9a-tetrahydro-4phenylbenz f isoindoline; mp hydrochloride 243-244 C. PRI me R 2. (Over RS, 4SR, 9aSR) -6-chloro- (4-p-chlorophenyl) -3a 4.9.9a-tetrahydrobenz f isoindoline-2-trifluoroacetate. , A solution of 30 g of M, N-bio- (trans-p-chloro-aminate) -trifluoroacetamide in 600 ml of o-dichlorobenzene is heated to boiling for 16 h under argon at reflux and then evaporated: The residue is chromatographed on 250 g of silica gel with benzene . The filtrate gives the title compound as a residue; m.p. 107-112С (after crystallization of the mixture, simple zirr-pentane). The K-bis- (trans-p-chlorocinnamyl) -trifluoroacetamide used as the starting material Y can be obtained analogously to example 3 by alkylation of N-trans-p-chlorocinnamide trifluoroacetamide by trans-sc-p-chlorocinnimyl bromide. Analogously to Examples 1 and 2, from the corresponding compound unsubstituted on the N atom and acetone, the compound (Over RS, 4SR, 9aSR) is obtained. Over, 4.9, 9a-tetrahydro-2 isopropyl-4-phenylbenz f isoindoline; m.p. acid maleine 150-158 C. By analogy with example 2, the following compounds are obtained from the corresponding compounds N not substituted on the atom N and formaldehyde: (Over RS, 4SR, 9aSR) -7-chloro-4- (., chlorophenyl) -3a, 4, 9,9a-tetrahydro-2-methylbenz f isoindoline; m.p. bis- (base) -naphthalene-1,5-disulfonate 244-248 ° C; . (Over RS, 4SR, 9aSR) -6-chloro-Za, 4, 9, 9a-tetrahydro-2-methyl-4-phenylbene if i eo and Ndoline; t, pl. hydrochloride 231-233C; (9aRS) -9,9a dihydro-2-methyl-3-phenylbene f isoindslin; m.p. acid maleic 158-162 0. By analogy with example 2, it is obtained from the corresponding unsubstituted at atom N compounds and acetaldehyde (a); (Over RS, 4SR, 9aSR) -2-ethyl-6-chloro-za., 4.9, 9a-tetrahydro-4-phenylbenz f isoindoline; mp. hydrochloride; 19,200 C; .. butyric aldehyde (b) g (After RS, 4SR, 9aSR) -2-p-butyl-6-chloro-For, 4.9,9a-tetrahydro-4-phenylbenz f isoindoline; m.p. fuma1rata 164-165 ° G ;. acetone (b): (3a-RS, 4SR, 9aSR) -6-HLOR-2-IZOpropyl-Za, 4,9,9a-tetrahydro-4-phenyl isoindoline; t. pl. - hydrochloride 243-244S. PRI me R 3. (For RS, 4SR, 9aSR For, 4.9, 9a-tetrahydro-4-phenylbenz f isoindoline. 22.3 g (For RS, 4SR, 9aSR) For, 4, 9.9a-tetrahydro-4phenylbenz f and iso Doline-2-trifluoroacetamide is dissolved in 3N methanolic potassium hydroxide solution. The mixture is stirred for 30 minutes at room temperature, then poured onto water and the methylene chloride is extracted, the extract is dried over sodium Clf, the solution is evaporated and the residue is crystallized from methylene chloride-pentane, the title compound is obtained; mp 136-138 C.; Needed as a starting material; (Over RS, 4SR, 9aSR) Over, 4, 9, 9a-tetrahydro-4-phenylbenz .f isoindoline-2-trifluoroacetamide is obtained, for example, as follows. Solution, 310 g of K, L-bis- (trans-cyanamyl) -trifluoroacetamide in á-o-dichlorobenzene is heated to boiling for 16 hours in an argon atmosphere under reflux and then evaporated. The residue gives a crystallisation from methylene chloride-pentane (Over RS, 4SR, 9aSR) Per, 4.9, 9a-te rahidro-4-phenylbenz f} isoindoline-2-trifluoroacetamide; m.p. LZO-ERS C IR spectrum (CH2Clj) 1690 cm, no bands at 950-9.90 cm. Required as the starting product L, N-bis- (trans-cinamide) -trifluorocetamide is obtained as follows. To soak 30.2 g of sodium hydride in 540 ml of hexamethylphosphoric triamide, a solution of 275 g was added dropwise with cooling and stirring. S-cinnamyl trifluoroacetate in 600 ml of hexamethylphosphoric acid triamide. After the end of the gas slurry, a solution of 248.5 g of tin-amyl bromide in 540 ml of triacid hexamethylphosphoric acid is added dropwise and the mixture is stirred for 16 hours at 25 seconds. After that, the reaction mixture is poured onto water. And extracted with ether. The ethereal solution, dried over sodium sulfate, is evaporated and the oily residue is chromatographed with toluene on 1.5 kg of silica gel. Upon evaporation, the filtrate gives N, N-bis- (trans-ciniamyl) -trifluoroacetamide as an oily residue. IR spectrum (CHjClg) 690, 968 cm. Ordinary conditions are also obtained by reduction (RS, 4SR, 9aSR). For 4,9,9a-tetrahydro-4-phenylbenz f isoindoline-2-p-toluenesulfonamide the target compound. Required as a starting material (Over RS, 4SR, 9aSR) Over 4.9, 9a-tetrahydro-4-phenylbenz f isoindoline-g2-p-toluenesulfonamide was prepared as follows. A solution of 2 g of N, N-bis- (trans-cinnamyl) -p-toluenesulfonamide in 200 ml of dichlorobeisol is heated to boiling for 48 h under argon at reflux and then evaporated, and get (For RS, 4SR, 9aSR ) Over, 4.9, 9a-tetrahydro-4-phenylbenz ff isoindoline-2-p-tolufl sulfonamide as a residue, melting temperature after crystallization from ether-pentane 185-187 ° C. Analogously to Example 3, the following compounds of formula II are prepared using the appropriate starting materials: (Over RS, 4SR, 9aSR) -6-chlorop-4- (4-chlorophenyl) 3a, 4.9, 9a-tetrahydro-benz f isoiidoline m.p. 133134С; (Per RS, 4SR, 9aSR) -6-fluorop-4- (p-fluorophenyl) -3a, 4.9.9a-tetrahydrobenz f isoindoline; tol. hydromaleicate 134-13bS; (Over RS, 4SR, 9aSR) -7-chloro-4- (methylchlorophenyl) 3a, 4,9,9a-tetrahydrobenz f isoindoline; m.p. hydromaleicate 166-168 C; (For RS, 4SR, 9aSR) For 4,9,9a-tetrahydro-6-methyl-4- (p-telil) -benz f isoindoline; m.p. 129-132 ° C; (Per RS, 4SR, 9aSR) Per, 4.9, 9a-tetrahydro-6-methyl-4-phenylbenz f isoindoline; . m.p. hydrochloride 174176 ° C; (3a.RS, 4SR, 9aSR) Za, 4,9,9a-tetrahydro-7-methyl-4-phenylbenz f isobutol "n; m.p. hydrochloride 225-227 C; (Over RS, 4SR, 9aSR) -6-hlop-Za, 4, 9,9a-tetrahydro-4-phenylbenz-isoindoline; t. hydrochloride 205207 C; (For RS, 4SR, 9aSR) For, 4,9,9a-tet ragilro-4-fenilbene f isoindoline; m.p. hydrochloride 25b-258C; (For RS, 4SR, 9aSR) For, 4,9,9a-tet rahidro-b-methyl-4-phenyl6enz f isoindoline; t, mp, hydrochloride 215 i (Over RS, 4SR, 9aSR) Over, 4.9, 9a-tet rahydro-7-methyl-4-phenylbenz f isoindoline; m.p. hydrochloride salt 22623С; , (As RS, 4SR, 9aSR) -b-chloro-Za, 4, 9.9a-Tetrahydrb4-phenylbenz f ysoindoline; m.p. 144-145С; (9aSR) -9,9a-dehydro-4-phenylbenz f isoindolic; m.p. of tidrololida 238-243S (decomposition). P r and me p 4. (Over RS, 4SR, 9aSR) -b-chloro-Za, 4, 9.9a-tetrahydrophenylbenz f isoindoline. A mixture of 8.8 g (Over RS, 4SR, 9aSR) -6-chloro-Ea, 4.9, 9a-tetrahydro-2-feeds carbonyl-4-phenylbenzene (fj isoindole: A 260 ml of methanol and 42 g of 50% growth The caustic soda is heated to boiling in a nitrogen atmosphere for 15 hours with a reflux condenser, then P1) 0abd concentration and dilution with methyl chloride. Upon evaporation of the washed and in the dried organic phase, the indicated compound is obtained with mp. 144-145C, (after crystallization from ethanol-pentane mixture) -. Used as an outcome ;; nog6 yaterial (Over RS, 4SR, 9aSR) -b7chlor-3a, 4,9,9a-tetrahydro-2-phenoxycarbonyl-4-phenylbenz f isrene-. : valleys ndJiy itatoT follows. A solution of 9 g (Per IZ, 4SR, 9aSR) -2-methyl-6-chloro-Per, 4,9,9a-tetrahydro-4-phenylbenz f ioindoline in 90 ksh 1motylene chloride is mixed at a temperature of 0 ° C 3, 65 ml of phenyl ether, 1 1 1 1 symmunic acid, are stirred for 16 hours at room temperature, 3 hours later, and 3 hours are passed through. a solution of edcrgo, 2 n. solution of hydrochloric acid and water, cyuiaT And evaporated. Oily Osta-gsk is chromatographed with a mixture of toluene-acetic ether (1: 1) on 1OO-fold amount of silica gel, and you get (Over RS, 4SR, 9aSR) Over / 4,9,9a-tetrahydro-2-phenoxycarbonyl-4-phenylbene f isoindoline ; m.p. 130134 С (after crystallization from the last ether). . ..- ,, ;;;. g.; .;, Frozen. (Per RS, 4SR, 9aSR) -6-fluoro-4-p-fluorophenyl- (Per, 4.9.9a-tetrahydrobenz f isoindoline-2-three pho: adCetamid.;;. ---- | (heGyoNo compound with mp 173Cb ° C (crystallization cation-of. ether) is obtained as psibeib in example 3, by thermal cyclization of N, N-6HC- (trans-p-fluoro-cin-amide) trifluoroacetamide .. Required as the starting material N, N-bis- (trans-p-fluorocinnamide) -trifluoroacetamide with a melting point of 7779 s (after crystallization from chloroform) is obtained by the method described in example 3 from N-p-fluorocinnamide trifluoroacetamide and p-fluorocinnamyl bromide. For RS, .4SR, 9aSR) -7 -chloro-4- ((-hprophenyl) -3a, 4,9,9a-tetrahydrobenz (f) isoindoline-2-trifluoroacetamide. The final is obtained in the form of an oil by thermal cyclization of N, N-6Hc- (trans-l-chlorocinnamide) -TrifluoroacetamYDA, as described in Example 3, and purified by chromatography on silica gel (19: 1 mixture of benzo-ethyl acetate). Necessary as the starting material is S, CH-bis- (trans-.-chlorocinnamide) -trifluorocetamide (oil) prepared in the manner described in example 3 from N-methachlorcinnamyl trifluoroacetamide and m-chlorocinnamylbromide. . Example7. (For RS, 4SR, 9aSR) -Tetraghydro-6-methyl-(4-p-tolyl) -benz. f isoindoline-2-trifluoroacetamide. target compound with so pl. 110-, 113 ° C (after crystallization from a mixture of ether-pentane) are prepared, as described in Example 3, by thermal cyclization of S, M-bis- (trans-p-methylcinnamide) -trifluorocetamide. . N, N-6HC- (trans-p-methylcynamyl) -trift1eracetamyl (oil) required as starting material is obtained from the Pisannil method in example 3 from N-p-methylcinnamyl trifluoroacetamide; th and methylcinnamylbromide. Example8. (9aRS) 9,9a-dihydro-4-phenylbenz f isoindoline-2-trifluoroacetamide., -Bench solution 218 g of N- (trans-cinnamyl) -N- (phenyl-2-propynyl) -trifluoroacetamide in 4.4 l of o- Dichlorobene — The mixture is heated to boiling in an atmosphere of argon for 5 hours with a reflux condenser, and then evaporated. The residue gives crystallization from an ether-pentane mixture of a short-term compound; m.p. 195-197; C. Usage1 11th as the initial material N- (trans-cinnamyl) -. -N- (3-Phenyl-2-propynyl) trifluoroacetamide can be obtained by alkylation of N- (trans-cinnamyl) trifluorocetamide with 1-bromo-3-phenyl-2 propin. Claims of the invention. Method for producing di- or tetrahydrobenz tf yzoindylines of the general formula in which R and R are the same or different and mean a hydrogen atom, halogen or alkyl group of carbon atoms from 1 to 4; X and Y or both signify a hydrogen atom, in which case ring B and C are connected to the cis configuration. Alternatively, X and Y together form an additional K bond: means primary or secondary alkyl group with the number of carbon atoms from 1 to 5; OR their optical isomers, or racemic mixtures of these optical isomers, or their salts, from 1 to 2 and the fact that the compound of the form is where H, Rj X and Y have the above values, is alkylated by aldehyde or ketone with carbon atoms from 1 to 5 carbon atoms, in the presence of formic acid at elevated temperature and the floor, scientific compounds are isolated in the form of optical isomers, or racemic mixtures of these optical isomers, or their salts. 2, the method according to claim 1, wherein the reaction is carried out at the boiling point of the reaction mixture, and that ff, -alkylation is carried out. Priority on the grounds of 09/29/72 when R, Rg, X and Y are hydrogen, with X and Y being in the trans position. 08.08.73 when R, Rj, X and Y mean halogen or alkyl group with the number of carbon atoms from 1 to 4, X and Y or both mean a hydrogen atom, and in this case, rings B and C are connected by cis configuration, or X and Together form an additional bond. R 3 means a primary or secondary alkyl group with the number of carbon atoms from 1 to 5. Sources of information taken into account in the examination 1. Fizer L., Fizer M. Organic Chem. Ed. Chemistry, M., 1966, p. 591.