SU493964A3 - The method of isoindoline derivatives or their salts - Google Patents

Description

and Ri - Rg have the same meaning as Ri-Rg, except that they cannot mean hydroxyl groups, but additionally they mean 2-tetrahydropyranyloxy groups, and the 2-tetrahydropyranyloxy groups, which are in the appropriate case, are converted into hydroxy groups. In the resulting compounds, the methoxy, ethoxy, or methylenedioxy groups can be converted into hydroxy groups or vice versa, and the resulting products are separated as free bases or their salts with acids.

The cyclization of the compounds is carried out using a mineral acid, or an organic acid, or an acid anhydride. In this case, it is possible to operate under aqueous or non-aqueous conditions, it is advisable to carry out the reaction in an inert gas (nitrogen) atmosphere. The presence of an inert organic solvent is positive, but not necessary. If it is necessary to use inert organic solvents, it is advisable to use ethers like tetrahydrofuran, or hydrocarbons like heptane, hexane or benzene. Mineral acids suitable for cyclization are sulfuric, hydrogen halide, hydrochloric, hydrobromic and phosphoric. Preferably, the cyclization is carried out using organic acids or organic acid anhydrides. It is advisable to use acetic acid, trifluoroacetic acid, or acetic anhydride, or trifluoroacetic anhydride. When using mineral acid, the cyclization is expediently carried out at temperatures of 70-120, preferably at the boiling point of the reaction mixture. The duration of the reaction varies from 1 to 48, preferably 18-24 hours. When using an organic acid or an anhydride of an organic acid, it is advisable to carry out the cyclization at temperatures from -10 to + 10 ° C, preferably from -5 to + 5 ° C, for 1-5 hours. In the case of using the compounds of structural formula I containing 2-tetrahydropyranyloxy groups as starting materials, compounds of structural formula I containing hydroxyl groups in the corresponding place are obtained. During the reaction, 2-tetrahydropyranyloxy groups are cleaved off and hydroxyl groups are formed.

When using compounds of structural formula II containing alkoxy or methylenedioxy substituents, strong acid conditions should be avoided as starting compounds in order to reduce the possibility of cleaving the alkoxy or methylenedioxy group. Therefore, for example, it is advisable to use an organic acid or an anhydride of an organic acid, if we proceed from the compounds of structural formula II containing alkoxy or methylenedioxy substituents.

Compounds of structural formula 1 containing C1 or 2-alkoxy or methylenedioxy substituents can also be obtained in such a way that compounds of structural formula I containing hydroxyl groups in the appropriate place (two of adjacent C atoms are hydroxyl groups, if required to obtain compounds of structural formula I containing methylenedioxy substituent) in

10 as alkali or alkaline earth metal salts, for example, in the form of sodium salt or disodium salt, are reacted with an appropriate alkyl chloride, alkyl iodide, or preferably 15-bromide, or, if required, compounds of structural formula I containing a methylenedioxy group with methylene dichloride, diiodide, or predominantly dibromide. The reaction interaction is carried out in

20 in the presence of metals of the first transition series, for example copper, cobalt, or iron in the elemental or ionic form. The reaction is expediently carried out in an organic organic solvent, for example dioxane,

25 tetrahydrofuran, dimethylacetamide or dimethylformamide, or in an aromatic hydrocarbon, such as benzene or toluene, at a temperature of 50-200, preferably 100-150 ° C for 5-24 hours.

Example 1. Spiro- (10,11) -dihydro-5H-dibenzo-a, -cyclohepten-5: G-iN - methylisoindoline. A. 2- (10-11 - dihydro-5 - hydroxy - 5H - di5 benzo and a-cyclohepten-5-yl) -Y - methyl benzamide. 15.2 g (0.108 mol) of N-methylbenzamide and 150 ml of dry tetrahydrofuran are served at room temperature into a flask with a stirrer, a dropping funnel, a reflux condenser and a gas-inlet tube under a nitrogen atmosphere. The reaction flask is immersed in an ice bath and cooled to an internal temperature of about 5 ° C. Then, displacing, 152 ml of a solution of 1.6 M n-bu5 tillity (0.240 mol) in hexane are added dropwise over about 1 hour, while the temperature is maintained below about 8 ° C. The resulting red dilithium salt is placed for another 1 hour at 5 ° C, then a solution of 22.5 g (0.108 mol) of 10,11-digndro-5H-dibenzoate (-cyclohepten-5-one in 75 ml) is added dropwise. anhydrous tetrahydrofuran for about 45 minutes, maintaining the temperature from -10 to - (- 10 ° C. The resulting reaction mixture is stirred for 1 hour at 5 ° C, then it is exposed to 100 ml of a saturated aqueous solution of ammonium chloride, maintaining the temperature below 10 ° C The layers are separated, the tetrahydrofuran layer is dried over

0 anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting oil is triturated with cold ether and filtered to give 2- (10,11-dihydro-5-hydroxy-5H-dibenzo a, c-cyclohepten-5-yl) -N-methylbenzamide,

m.p. 188-19GS (with gas formation),

B: 2- (10,11-dihydro-5-hydroxy-5H - dibenzo a, c -cyclohepten-5-yl) - N - methylbenzylamine. 1.52 g of lithium aluminum hydride

(0.40 mol) and 100 ml of anhydrous tetrahydrofuran at room temperature in a flask with a stirrer, reflux condenser, gas tube in a nitrogen atmosphere. While stirring, 8 g of 2- (10,11-dihydro-5-hydroxy-5H-dibenzo-a, d-cyclohepten-5-yl) -Y-methylbenzamide dissolved in 50 ml of anhydrous tetrahydrofuran is added dropwise in 30 minutes. . The resulting mixture is heated for 18 hours under reflux to boiling, then cooled in an ice bath. Thereafter, 9 ml of ethyl acetate is added dropwise over 10 minutes, then 3 ml of 2N aqueous solution is added dropwise over about 10 minutes. sodium hydroxide and 4.5 ml of water.

The resulting mixture was dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo to form a main compound.

B. Spiro- (10,11-dihydro-5H-dibenzo - a, d cyclohepten-5: 1-methylisoindoline).

7 g of the Bam alcohol obtained in Example 1 above and 150 ml of 2 M sulfuric acid are fed at room temperature to a flask with a stirrer, a reflux condenser and a gas inlet tube under a nitrogen atmosphere. Then stirred, the reaction mixture was cooled with ice, brought to the main reaction by controlled addition of solid KOH and extracted twice with methylene chloride to 150 ml twice. Methylene chloride solutions were combined, washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. After recrystallization of the oily residue from ethyladetate, spiro- (10,11-dihydro-5H-dibenzoate with cG -cyclohepten-5: 1 - methylisoindoline) crystals are obtained; m.p. 131-113 ° C.

Example 2. Spiro- (10,1 l-dihydro-5H-dibenzo-o, d-cyclohepten-5: I-N - methylisoindoline), hydrochloride.

A solution of 5 g of spiro- (10,11-dihydro-5H-dibenzo, α-cyclohepten-5: 1-H - methyl isoindoline) in 100 ml of ethanol is cooled to 5 ° C and saturated with gaseous HC1. After that, the solvent is removed, the residue is reacted with ether, thus obtaining spiro- (10,11-dihydro-5H-dibenzo, a-y-cyclohepten-5: G - Nmethylisoindoline) in the form of hydrochloride (white, solid); m.p. 227.5-228.5 ° C.

Example 3

A. Analogously to Example 1, A, but using approximately equivalent amounts: (i) N-ethylbenzamide,

(Ii) 4-methoxy-y-methylbenzamide,

(Iii) 4-M-methylbenzamide or

(Iv) 4- (2-tetrahydropyranyloxy) - N - methylbenzamide instead of N-methylbenzamide,

receive:

(I) 2- (10,11-dihydro-5-hydroxy-5H-dibenzo u, d -cyclohepten-5-yl) -N-ethylbenzamide,

(Ii) 2- (10,11-dihydro-5-hydroxy-5H-dibenzo a, d -cyclohepten-5-yl) -4-methoxy-N-methylbenzamide,

(III) 2- (10,11-dihydro-5-hydroxy-5H - dibenzo a, d -cyclohepten-5-yl) -4, N-dimethylbenzamide,

(IV) 2- (10,11-dihydro-5-hydroxy - 5H - dibenzo a, cf -cyclohepten-5-yl) -N-2 -2 - (tetrahydropyranyloxy) -N-methylbenzamide.

Analogously to example 1, A, but using approximately equivalent amounts:

(V) 5P-dibenzo-a, d -cyclohepten-5-one,

(Vi) 10,11-dihydro-2,3-dimethoxy-5H-dibenzo-a, y-cyclohepten-5-one,

(VII) 10,11-dihydro-2,3-methylenedioxy - 5Pdibenzo-a, d -cyclohepten-5-one

instead

10,11-dihydro-5P-dibenzo - a, d - cyclohepten-5-one, receive:

(V) 2- (5-hydroxy-5H-dibenzo - a, d - cyclohepten-5-yl) -N-methylbenzamide,

(Vi) 2- (10,11-dihydro-5-hydroxy-2,3-dimethoxy-5H-dibenzo, α-cycloheptan-5-yl) - N - methyl benzamide or

(Vii) 2- (10,11-dihydro-5-hydroxy-2,3-methylenedioxy-5H-dibenzo, a2-cyclohepten-5-yl) N-methylbenzamide.

B. Analogously to Example 1, B, by replacing 2 (10,11-dihydro-5-hydroxy-5H-dibenzocyclohepten-5-yl-methylbenzamide, approximately equivalent amounts of compounds IV are obtained:

(I) 2- (10,11-dihydro-5-hydroxy-5H-dibenzo a, d -cyclohepten-5-yl) -N-ethylbenzylamine,

(I) 2- (10,11-dihydro-5-hydroxy - 5H - dibenzo, rf-cyclohepten-5-yl) -4-MeTOKCH-N- - methylbenzylamine,

(III) 2- (10,11-dihydro-5-hydroxy-5H - dibenzo a, d -cyclohepten-5-yl) -4, N-dimethylbenzylamine,

(IV) 2- (10,11-dihydro-5-hydroxy-5H - dibenzo a, d -cyclohepten-5-yl) -4- (2 - tetrahydropyranchioxy) -N-methylbenzylamine,

(V) 2- (5-hydroxy-5H-dibenzo a, cr - cyclohepten-5-yl) -N-methylbenzylamine,

(Vi) 2- (10,11-dihydro-5-hydroxy-2,3-dimethoxy5H-dibenzo, c-cyclohepten-5-yl) - N - methylbenzylamine,

(Vii) 2- (10,11-dihydro-5-hydroxy-2,3-methylenedioxy-5H-dibenzo, and th - cyclohepten - 5yl) -N-methylbenzylamine.

B. Analogously to Example 1, B with the replacement of 2 (10,11-dihydro-5-OXII-5H-dibenz-a, cG | -cyclogen-5-yl) -N-methylbenzamide with approximately equivalent amounts of one of

compounds of point B

receive:

(I) spiro- (10,11-dihydro - 5H - dibenzo a, y-cyclohepten-5: D - N - ethylisoindoline) t. Pl. 93-94 ° C

(P) spiro - (10,11-dihydro-6-markOI-5N-dibenzo-a, c -cyclohepten-5: G - N - methylisonendndoline); t, mp, 159-IGIX, (III) spiro- (10,11-dihydro-6 - methyl - 5Nbibenzo, -cyclohepten-5: G - N - methylisoindoline); m.p. 139.5-141 ° С, (IV) spiro- (10,11-dihydro-6-methyl-5N-dibenzoate, c -diclohepten-5: 1-N-methylisoindoline); m.p. 183.5-187 ° С, (V) spiro- (5H-dibenzo, and th - cyclohepten5: I-N-methylisoindoline); m.p. 174-178 ° C, (VI) spiro- (10,11-dihydro-2,3-dimethoxy5H-dibenzoate, y-cyclohepten-5: 1 — N — methylisoindoline); m.p. 120-12GS, (VII) spiro- (10,11-dihydro-2,3-methylenedioxy-5H-dibenzoate, d-cyclohepten-5: GN-methylisoindoline; mp 139-14 GS. Example 4. Spiro- (10,11-dihydro-b-hydroxy5H-dibenzoate, c -cyclohepten - 5: G - N-methylisoindoline). A solution of 3.41 g (0.001 mol) of spiro- (10,11-dihydro-b- methoxydibenzo - a, d - -cyclohepten5: lN-methylisoindoline) in 40 ml of 48% hydrogen bromide and 40 ml (g) of acetic acid are heated under reflux for 19 hours until boiling. Then the reaction mixture is poured onto ice and the resulting solution is added by adding under the control of solid KOH, brought to the main reaction. The solution is extracted with chloroform, dried over magnesium sulphate, evaporated in vacuo and triturated with ethyl fir to give spiro (10,11-dihydro-6-oxy-5H-dibenzo-a, c -cyclohepten-5: IN-methylisoindoline); . pl. 183-187 ° C (with decomposition). Example 5. Spiro- (10,11-dihydro-2,3-methylenedioxy-5H-dibenzo - a, d - cyclohepten, 5: | G – N-methylisoindoline) A mixture of 3.57 g (0.01 mol) of spiro- (10,11-dihydro-2, 3-dioxy-5H-dibenzoate, - cidlohepten5: G-N-methylisoindoline), 30 ml of dimethylformamide, 0.5 g of copper oxide, 4 g of anhydrous potassium carbonate and 2.26 g (0.012 mol) of methylene bromide are heated, stirring with reflux for about 7 hours under nitrogen. Then the reaction mixture is cooled and filtered, the filtrate is evaporated in vacuo. The residue is dissolved in ether, the ethereal solution is washed with 5% sodium hydroxide solution and water, dried over magnesium sulfate, filtered and evaporated to obtain Spiro- (10,11-dihydro-2,3-methylenedioxy-5H-dibenzo) by recrystallization from ethyl acetate - a, d - cyclohepten5: IN-methylisoindoline); m.p. 139-141 ° C. The same substance is obtained using the above method, however, when replacing the diol disodium salt) diol (obtained in the usual way by affecting the diol with sodium hydroxide in dimethylformamide). Example 6. Spiro- (10,11-dihydro-2,3-dimethoxy-5H-dibenzo, th (α-cyclohepten - 5: 1N-methylisoindoline). Analogously to example 5, replacing methylene bromide with approximate equivalent amounts of methyl iodide. Spiro (10,11-digidro-2,3-dimethoxy-5H-dienzoa, c -cyclohepten-5: IN-methylisoinoline); mp 120-12 ° C. Subject of the Invention A method for producing isoindoline derivatives of the formula I, where X is the groups of structural formulas CHa-CHs-or R are an alkyl group with 1 to 3 carbon atoms; RI-Re is the same or different, and each means hydrogen, hydroxyl, methoxy or ethoxy, and two of the substituents RI-Rs, which are adjacent, can mean the methylenedioxy group; R and Rg are the same or different and each means hydrogen, hydroxyl, methoxy, ETOXI, methyl or ethyl, and Rg is hydrogen, hydroxyl, methoxy or ethoxy group, with at least one of the substituents RI, Ra and Rs, at least one of the substituents R4, Rs, Re, at least one of the substituents R, Rs, Rg means hydrogen, and no more than three of the substituents RI-Rg have a different meaning than hydrogen, or their salts, characterized in that Compounds of general formula II are RN-CHf H where R and X are as defined above, and RJ-Rg have the same meaning as Ri-Rg, except that they cannot mean hydroxyl groups, but additionally mean 2-tetrahydropyranyloxy groups, subjected to cyclization by heating with a mineral or organic acid or acid anhydride in an inert gas atmosphere, such as nitrogen, followed by isolation of the target product as a base or by transferring it into a salt, or meth9 OXY, ethoxy or methylenedioxy groups are converted into oxy groups Or iaoborot known techniques. The priority is based on the following signs: July 13, 70, where the 5 .Rg is the same or different and each means hydrogen, methoxy or ethoxy, and two of the substituents Ri-Rg that are adjacent, together can mean methylenedioxy; 03/08/71: Ri-Rg means hydroxy.