SU495823A3 - Method for producing substituted dibenzocycloheptenes - Google Patents

Description

sulfur or salt, preferably 1-5M HoSO; at the same time, a ray of nitrogen is applied to the nitric acid., For the removal of water, iodine, phos yrox chloride, thionyl chloride are also applicable. alkyl or aryl sulphonyl chloride such as methanesulfonic chloride or benzosulfonyl chloride, or a solid inorganic acid or Lewis acid such as potassium bisulfate, boric acid, alumina or silicon dioxide. In the case of phosphorus oxychloride, thioiyl chloride, or alkyl alkyl or arylsulfonyl chloride, the reaction is preferably carried out in the presence of a coupling acid, such as lower tertiary alkylamine, such as triethylamine. When using one of these water splitting agents or solid inorganic acid and. Lewis acids reaction is preferably carried out in inert Eo: 1 organic solvent, and the hydrocarbon hydrocarbon is benzene or toluene. The reaction is expediently carried out at temperatures from 50 ° C to a temperature of:; ipeii reaction mixture, preferably at boiling. Duration of interaction is 1-24 hours, and preferably 1-4 hours.

The desired product is isolated in a known manner in the free form as a salt, hydrochloride, sulfate, phosphate, succinate, benzenesulfonate or maleate, as well as isomers, which are separated by known methods into optically active antipodes.

EXAMPLE 1. (2-Dimethylaminoethyl) - | 3 Oxypheethyl-L-methylbenzamide.

Equipped with a bourgeois, canal void, reflux condenser and gas tube, the reaction vessel is kept in a nitrogen atmosphere, loading at a temperature of 40.4 g (0, mol) o-.methyl - // - methylbenzamide, as well as 250 ml of anhydrous tetrahydrofioan. Then the vessel is cooled in an ice bath to an internal temperature of 5 ° C. Stirring is stopped, 360 ml of 1.6 M c-lithium butyl (0.616 mol) in hexane is added over 1 h over 1 h, maintaining the temperature below 8 ° C. The red dilithium salt thus obtained is stirred at 5 ° C for 1 hour, but the reaction vessel is immersed in a bath of dry ice-acetone, cooled to an internal temperature of -30 ° C. A solution of 49.7 g (0.28 mol) of 3-dimethylaminonroniophenone in 140 ml of anhydrous tetrahydrofurap is added dropwise to the cooled reaction mixture over 45 minutes, maintaining the temperature in danazone from -30 to -20 ° C. The resulting reaction mixture is stirred for 1 h. At 25 ° C, then the temperature is allowed to rise to -10 ° C for 1 hour, after which the initial mixture is treated with 200 ml of a saturated aqueous solution of ammonium chloride, maintaining the temperature below 0 ° C. Formed at the same time

- P - oxyphenethyl-A-Mstilben: am 1d and so on. Pl. 139.5-140,

G1 p and m e r 2. 3- (2-Dimethylaminoethyl) -3,4 d; ) G ;; draw-3-feii; 1isok marin.

16.3 g (0.05 mol) of 2- | p- (2-dimethylaminoethyl) -3-hydroxyphenethyl-L-methylbenzampd, and also 170 ml o-dichlorobenzene. Then the reaction mixture is stirred and heated to boiling point for 8 hours. The excess o-dichloro-isol is distilled off in vacuo, the resulting oil is recrystallized from ether to give 3- (2-dimethylaminostil) -3,4-dihydro-3 - feiyl isocouria with T. Il. 95.0-95.5 ° C.

Example 3. 10- (2-Dimethylnn tnl-10, 11-dihydro-5-methylene - 5H - dibenzo (a,) cyclohepten.

a) 2-p- (2-dimethylaminoethlphen) phenethyl t-benzoic acid hydrochloride.

A solution of 14.75 g (0.05 mol) of 3- (2-dimethyllamine: oethyl) -3,4 - dihydro-3-feiyl isocoumarin in 150. Ml of ethanol, containing 1 g of 10% padlpdn on coal, at 3, 5 kg / cm and room temperature before foot absorption is 1 eq. hydrogen. The mixture is then filtered and evaporated to get hydrochloride (2-dimethylaminoethyl-phenylethyl-benzoic acid with mp 152--154 ° C.

b) 10- (2-Dimethyl1Minoethyl) -10,11 - dihydro-5P-dibenzo (a, d) cyclogenten - 5 - it is chloro-indigrate.

A mixture of 14.75 g (0.05 mol) of 2 - ((2-dimethylamino-ethyl) -phenethyl-benzoic acid hydrochloride is heated to 110 ° C for 6 hours, after which the mixture is allowed to cool to room temperature and then stirring the solution obtained is made alkaline with —nr ice-cooling KOH, then extracted with methylene chloride. The chlorine methylene phase is washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue is dissolved in isonpropanol, then treated with gaseous hydrogen chloride. otfil trovyvayut and nerekristallizovyvayut from isopropanol to give 10 (2-dnmetnlamnnoetil) -10,11-dngidro-5H - dibenzo (a, () tsiklogenten - 5 - it -.. the hydrochloride, mp 188-190 ° C.

In the same way, but using 1 eq. iron dichloride instead of the niphosphoric acid, get the same product.

In the same way, the same product is obtained, starting from iron dichloride and 2- (3- (2-dimethylaminoethne) chloride) phenethyl benzoic acid.

Similarly, but using 16.3 g of ethyl ester (2-dimethylaminoethne) phenethyl benzoic acid instead of 14.75 g of 2-p- (2-dimethylaminoethyl) phenylethyl benzoic acid hydrochloride, the same product is obtained.

c) 10- {2-D 1, l-methyl-amino-ethyl) -10,11-dihydro-5-methyl-5H-dibenzo (a, d) cyclohepten-5-ol.

Rasgvor 19.4 g (0.07 mol) 10- (2-dimethiclaminoethl) -10.11 - dihydro-5H - dibenzo {a, d) cyclohepten-5-one in 200 ml of diesel is kept under nitrogen atmosphere and cooled to - 5 ° C. To the resulting solution, 70 ml of 1.5 N are then added dropwise. lithium methyl (0.105 mol) in diethyl ether, stirring and maintaining the temperature of the pyge 0 ° C. Fifteen minutes after the end of the addition, the reaction is terminated by the addition of 50 ml of a saturated solution of ammonium chloride. The organic layer was separated, extracted with saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. The crystalline residue is recrystallized from methylene chloride / methanol (1/1); 10- (2-dimethylaminoethyl) -10,11-dihydro-5-methyl-5H-dibenzo (a, d) cyclohepten-5ol are obtained, m.p. 161.5-162 ° C.

Similarly to the above method, but using the appropriate amount of methylene chloride instead of lithium methyl at room temperature rather than at 0 ° C, the reaction time is 3 hours, not 15 minutes, the same product is obtained.

d) 10- (2-Dimetryplamp1-1Oethyl) 10,11 - dihydro-5-methylene-5H-dibenzo (a, d) cyclohepten.

A mixture of 8 g (0.027 mol) of 10- (2-dimethylaminoethyl) -10.11 - dihydro-5-methyl - 5H - dibenzo (a.1) cyclohepten-5-ol and 250 ml of 2 M H2SO4 is heated for 2 hours in ice bath, then adding solid KOH to alkalization. Then it is extracted with methylene chloride, the methylene chloride extract is washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The oily residue is distilled at 140 ° C (0.5 mmHg), the distillate formed at this time is dissolved in ethanol and treated with maleipic acid. The precipitate is filtered off and recrystallized from diethyl ether / ethanol (1/1) to give 10- (2-dimethylaminoethyl) -10, 11 -dihydro-5-methylene - 5H - dibenzo (a, d) cyclohepten in the form of a maleic acid salt, m.p. 171 - 172 ° C.

Similarly to the above method and using the appropriate amount of iron dichloride instead of sulfuric acid get the same product.

Example 4. 2- p - (2 - Dimethylaminoethyl) phenethyl benzoic acid.

In a well stirred suspension, 45 g of powdered zinc, 90 ml of concentrated ammonium hydroxide, 45 ml of water and 2 ml of copper sulfate are kept at 80 ° C, then 14.75 g (0.05 1 mol) of 3- (2-dimethylaminoethyl) - 3,4-dihydro - 3-phenylisocoumarin B 50 ml of ethanol for about half an hour. The resulting mixture is heated for half an hour to, while simultaneously introducing an ammonia gas stream. The mixture is filtered hot, the solids are thoroughly washed with 100 m /; ammonium hydroxide. The filtrates are combined, cooled and carefully injected: 1Cl 10: concentrated hydrochloric acid; (2-dimethylphenylethyl) fepethyl benzoic acid} is obtained, the hydrochloride of which melts at 152-154 ° C.

Example 5. This 1-ester (2-dpmethylaminoethpl) -phenethyl benzoic ester;

Discharge 29.7 g (0.1 mol) 2-G | 3- (2-dimethyl inoeth; 1 l) -pent1; l - benzoic acid in 200 ethanol is saturated with gaseous hydrogen chloride, the resulting mixture is heated under IS for 1 h. . The solvent is removed in vacuo, the residue is distributed with ether; o. ; i 2n. sodium hydroxide. The ether extract is dried and evaporated in a vacuum. get ethyl ester (2-dimethylamide 10til) - phenethyl - benzoic acid.

Example 6. 10- (2-Dimethylaminoethyl) -10, 11-dngidro-5-methylene-5P - dibenzo (0,) - cyclohepten.

To a mixture of 5 g of 0- (2-dnmethylaminoethyl) 10,11-dihydro-5-methylene-5H-dibenzo (a, d) cycloheptene maleate in 150 ml of methylene chloride was added 50 ml of 2N. sodium hydroxide. The mixture is shaken, methylene chloride is dried, filtered and evaporated in vacuo to give 10- (2-dimethylaminoethyl) -10, 11-hydroxy-5-methylene-5H-dibenzo (a, d) cyclohepten.

Example 7. The following compounds were prepared analogously:

a) 10- (2-Dimethylaminoethyl) - 10,11-dihydro-2, 7-dpfluoro-5 - methylene - 5H - dibenzo (a, rf) cpcloheptenmaleate;

b) 10- (2-dimetplaminoethyl) - 10,11-dihydro-7-fluoro-5-methylene - 5H-dibenzo (a, d) cyclohepten-maleate, so pl. 148.5 (up to 149.5 ° С);

c) 10- (2-diethylMinoethyl) 10,11-dihydro - 5 methylene-5P-dibenzo (a.d) cyclohepten.

Subject invention

The method of obtaining substituted dibenzocycloheptenes of general formula I

where RI is hydrogen, alkyl or alkoxy - each with 1-3 carbon atoms, or fluorine; R2 is hydrogen, alkyl or alkoxy - each

fluoromethyl with 1-3 atoms;

Ra and R alkyl with

atoms of their salts, different compounds of the general formula II

BUT

eight

where RI, R2, Rs, and R4 are as defined above, are dehydrated by conventional methods, followed by isolation of the target product with a known method in the form of axis or salt.

Priority by grounds:

06.02.72, where

RI is in 2-position;

Rs is in 7-position.

20.11.72, where Ri is also 3-position, and if R2 is not in 7-position, then Ri may also be in 2-position; R2 is in the 8th position, and if Ri is not in 2-Nozhogenpi, then R2 may also be B-7.