CS209396B1 - Process for the preparation of new 4-alkoxylated 5H-isoindolo [1,2-b] [3] benzazepin-5-ones - Google Patents

Abstract

4-Alkoxylated 5H-isoindolo[1,2-b][3]benzazepin-5-ones of the general formula I, (I), where R' represents an alkyl of 1 to 2 carbon atoms or a ring of 4 to 5 carbon atoms or a —(CH2)2—O-(CH2)2— group and their salts with pharmacologically harmless inorganic or organic acids, are valuable products and intermediates in the pharmaceutical industry. They are prepared from a substance of the general formula I, where R represents methyl, by the action of an alcohol and an alkali metal alcoholate of the general formulas ROH ROM, where R represents the same as in the formula and M is an alkali metal atom, by heating in a benzene solution. where R represents an alkyl of 2 to 4 carbon atoms, allyl or a 2-(N,N-dialkylamino)ethyl group of the partial formula II

Description

The present invention relates to a process for the preparation of novel 4-alkoxylated 5H-isoindolo [1,2-b] [3] benzazepin-5ones of formula I

wherein R represents alkyl of 2 to 4 carbon atoms, allyl or benzyl or 2- (N, N-dialkylamino) ethyl of the partial formula II (H),

wherein R 1 represents alkyl of 1 and 2 carbon atoms or a cycle of 4 to 5 carbon atoms, or - (CH ₂ ) ₂ -O- (CH ₂ ) ₂ - a group or salts of the corresponding tertiary amino group with pharmacologically acceptable inorganic or < organic acids. These may be valuable intermediates after the preparation of pharmaceutically valuable compounds.

10,11-Methylenedioxy-3,4,12-trimethoxy-7,8-dihydro-5H-isoindolo [1,2-b] [3] benzazepirine-5-one (1 H) is the starting material for the preparation of the compounds of formula I according to the invention. = CH ₃ ), which is one of the following: thermal decomposition of narceinimide methohydroxides (Z, Vesely, Holubek, J. Trojanek: Chem. And Ind.1973, 478). The process according to the invention is characterized in that the above-mentioned starting material is dissolved in a non-polar solvent, in particular in aromatic hydrocarbons, preferably. in a boiler heated in the presence of an alcohol and an alkali metal alcoholate of formulas ROH and ROM, wherein R is the same as in formula I and M is an alkali metal atom, preferably sodium. During a reaction of 30 minutes to 5 hours, a nucleophilic substitution occurs in which the alcoholate anion RO ^(_) , where R is the same as in formula I, replaces the methoxy group at the 4-position and thereby exchanges the alkoxyls (according to alcohol and alkali metal alcoholate). The reaction is general and all compounds of the invention of formula I are novel and have not been described in the literature.

The details of the production method according to the invention follow from the exemplary embodiment.

Examples

Example 1

1.4 g of sodium metal are dissolved in 70 ml of freshly distilled benzyl alcohol and the solution thus prepared is added to a solution of 1.4 g of 10,11-methylenedioxy-3,4,12-trimethoxy-7,8-dihydro-5H-isoindolo [ 1,2-b] [3] benzazepin-5-one (I, R = CH ₃ ) in 300 mL of benzene, and the mixture was heated to reflux for 4 h and solid potassium hydroxide tube. After cooling, the reaction mixture is shaken with 2 x 10% aqueous sodium hydroxide solution (100 ml each), 2 x 100 ml water, the organic phase is dried over anhydrous sodium sulphate and after distillation of benzene under water pump vacuum and benzyl alcohol under oil pump vacuum (below 10, 0 Pa) to give a residue (1.09 g) which is dissolved in a small amount of benzene and filtered through a column of 15 g of neutral alumina (Brockmann II-III activity) and washed with benzene. The benzene distillation residue was recrystallized from benzene-petroleum ether to give 0.1 g (78 g of ehromatographically uniform 4-benzyloxy-10,11-methylenedioxy-3,12-dimethoxy-7,8-dihydro-5H-isoindolo [1,2] -b] [3] benzazepin-5-one ₍ <R 1 = CH ₂ C ₆ H ₅ ), mp 132-134 ° C (1st fraction) and concentration of the mother liquor to 0.14 g of the second fraction, tt 130 - 132.5 ° C For C ₂₇ H ₂₃ NO ₆ (457.45) calculated: 70.88% C, 5.08% H, 3.06% N, found: 70.80% C, 5.29 % H, 2.82% N.

2. Example 2

In a 100 ml volumetric flask equipped with a reflux condenser and a solid potassium hydroxide-filled desiccant tube, dissolve 0.3 g of sodium metal (3.1 g) in 3.1 g of 2- (N, N-dimethylamino) ethanol (at 100-110 ° at the end C). A solution of 0.4 g of 10,11-methylenedioxy-3,4,12-trimethoxy-7,8-dihydro-5H-isoindolo [1,2-b] [3] benzazepin-5-one (i, R = CH) is then added. ₃ ) and the mixture is heated under reflux for 5 h. After cooling, the reaction mixture is shaken once with 15 ml of 10% aqueous sodium hydroxide solution, the benzene layer is washed twice with 15 ml of water each, dried over anhydrous sodium sulphate and distilled off the solvent to give Q, 47 g of crude product. amount of benzene and filter through a column of 10 g of neutral alumina (Brockmann II-III activity). Washing benzene is isolated 0.136 g of starting material (I, R = CH _3), further washing with chloroform yielded 0.32 g of product which was converted in benzene solution by adding the required 'amount of 3% hydrogen chloride in methanol hydrochlprid, which was recrystallized from acetone with little methanol. 0.16 g of 4- [2- (N, N-dimethylamino) ethyl] -10,11-methylenedioxy-3,12-dimethoxy-7,8-dihydro-5H-isoindolo [1,2-b] [hydrochloride] is obtained. 3] benzazepin-5-one (I, R = (CH ₂ ) ₂ N (CH ₃ ) ₂ ), mp 229-232 ° C.

Example 3

Dissolve in 10.0 g of 2- (N-piperidyl) ethanol

0.3 g of sodium metal after dissolution, a solution of 1,14 µg of 1,11-methylenedioxy-3,4,12-trimethoxy- 1,8-dihydro-5H-isoindolo [1,2-b] [3] ben209396 is added. of zzepin-5-one (I, R = CH ₃ ) in 50 mL of benzene and the mixture was heated to reflux for 5 h under a moisture seal. After cooling, the mixture is shaken once with 15 ml of 10% aqueous sodium hydroxide solution, the benzene layer is separated and washed twice with 15 ml of water, dried over anhydrous sodium sulfate and the solvent is distilled off in vacuo. 1.81 g of crude product is obtained, which is purified from residual starting material on a column of 18 g of silica gel (benzene-20% chloroform). It is obtained

1.3 g of 4- [2- (N-piperidyl) ethyl] -10,11-methylenedioxy-3,12-dimethoxy-7,8-dihydro-5H-isoindolo [1,2-b] [3] benzazepine- 5-one [I, R = (CH _{2) 2} -N QL t.1,114-118 ° C.

The hydrochloride of [I, R = (CH ₂ ) ₂ —N is prepared in a benzene solution by addition of the necessary amount of a 3% solution of hydrogen chloride in methanol and recrystallized from acetone with the addition of methanol, m.p. Mp 234-236 ° C.

Claims (1)

SUBJECT VYNALEZU A process for the preparation of novel 4-alkoxylated 5H-isoindolo [1,2-b] [3] benzazepin-5-ones of the general formula I or benzyl or 2- (N, N-dialkylamino) ethyl of the partial formula II wherein R 'represents alkyl of 1-2 carbon atoms, or a cycle of 4-5 carbon atoms or -CH ₂ -CH ₂ -O-CH ₂ -CH ₂ - or a salt thereof with pharmacologically nezávadnými'anorganickými or organic acids .vyznačený by the starting material of formula I, wherein R = CH _{3 is} heated to boiling in an inert solvent, in particular an aromatic hydrocarbon, preferably benzene in the presence of an alcohol and an alkali metal alcoholate of the formulas ROH and ROM, wherein R is the same as in formulas I and M an alkali metal atom, preferably sodium. -CH ₂ - CH ₂ - N R ' R '(II)