RU2108327C1 - Method of synthesis of 3-[2-(dimethylamino)-ethyl]-n-methyl- -1h-indole-5-methane sulfoneamide - Google Patents

Abstract

FIELD: chemical technology, organic chemistry. SUBSTANCE: invention describes method of decarboxylation of 2-carboxy-3-[2-(dimethylamino)-ethyl] -N-1H- -indole-5-methane sulfonamide (II) in the presence of the corresponding solvent and suitable catalyst under inert atmosphere and at temperature from 189 to 250 C. Method ensures to obtain 3-[2-(dimethylamino)-ethyl] -N-methyl-1H-ind- -ole-5-methane sulfoneamide (formula I), its salts and solvates showing effectiveness for migraine treatment. EFFECT: improved method of synthesis. 4 cl

Description

который в форме приемлемых с физиологической точки зрения своих солей или сольватов используют при лечении и/или предотвращении мигрени.The invention relates to a method for producing 3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide corresponding to the formula I:

which in the form of physiologically acceptable salts or solvates thereof is used in the treatment and / or prevention of migraine.

 In the patent ES-545810 a method for obtaining the target product by reducing various groups at position 3 of the indole, leading to the formation of the corresponding dimethylaminoethyl group.

 In the patent ES-552047 a method for obtaining the target product using the Fisher procedure for the synthesis of indole from the corresponding hydrazone is proposed.

 Patent ES-557480 proposes a process for preparing the desired product by substituting a substituted group with dimethylamine so as to form a dimethylaminoethyl group at position 3 in the indole ring (or UK Patent No. 2,124,120).

 Patent ES-557481 proposes a process for preparing the target product by reacting methylamine with a (mono) sulfonic acid derivative so as to form an N-methylmethanesulfonamide group at position 3 on the indole ring.

 Patent ES-55748 2 proposes a process for preparing the desired product by methylation of a methanesulfonamide group in N-methylmethanesulfonamide at position 5 in the indole ring and / or by monomethylation of a methylaminoethyl group or dimethylation of an aminoethyl group at position 3 in an indole so as to form the corresponding dimethylaminoethyl ethyl a group.

 Patent ES-557483 proposes a process for preparing the desired product by dehydrogenation of a suitably substituted indole to obtain the corresponding indole.

 In the patent ES-523039 proposed the same method as in the patent ES-552047, obtaining a class of derivatives of indole, which contains the target product.

 It is well known how to decarboxylate 2-carboxy indoles in an aqueous acidic medium (J. Chem. Soc., P. 4589 (1956)) or in quinoline in the presence of various copper catalysts, for example, copper pentafluorophenyl (J. Amer. Chem. Soc. T. 92, p. 3187 (1970)).

в присутствии соответствующего растворителя и подходящего катализатора в инертной атмосфере и при температуре 190 - 250^oC.The present invention provides a new method for producing 3- [2- (dimethylamino) ethyl] -N-methyl-IH-indole-5-methanesulfonamide, which contains decarboxylation of 2-carboxy-3- [2- (dimethylamino) ethyl] -N- methyl-IH-indole-5-methanesulfonamide of the formula (II):

in the presence of an appropriate solvent and a suitable catalyst in an inert atmosphere and at a temperature of 190 - 250 ^o C.

 Compound II can be prepared by reacting 2-carboalkoxy-3- (2-tolylsulfonylethyl) -N-methyl-IH-indole-5-methanesulfonamides with dimethylamine followed by saponification of the 2-carboxyalkoxy group.

 Decarboxylation of 2-carboxyindole II can be carried out in quinoline as the sole solvent or in a mixture with organic solvents such as triethylene glycol dimethyl ether, diphenyl ether, etc. in a stream of dry nitrogen.

 The reaction is carried out in the presence of an appropriate catalyst such as copper dust, monovalent copper oxide, monovalent copper chloride, copper chromite, copper pentafluorophenyl or a divalent copper salt of compound II used in a ratio of 5-10 mol% with respect to compound II.

The reaction can be carried out at a temperature of 190 - 250 ^o C, preferably at a temperature of about 205 ^o C.

 The target product was isolated using known techniques and purified by recrystallization.

 Example 1. Decarboxylation with quinoline and monovalent oxide of copper.

2 g (6 mmol) of 2-carboxy-3- [2- (dimethylamino) ethyl] -N-methyl-IH-indole-5-methanesulfonamide was dissolved in 20 ml of dry quinoline. After adding 40 ml (0.3 mmol) of monovalent copper oxide, the stirred suspension was heated to 250 ^° C. in a stream of dry nitrogen. The reaction mixture was maintained at this temperature until CO _{2 was} already emitted (30-40 minutes). The mixture was allowed to cool to room temperature and then filtered through decalite. The filtrate was concentrated by distillation of the solvent in vacuo to give a residue, which was suspended in 40 ml of dichloromethane and then filtered. The new filtrate was washed three times with 15 ml of a 10% aqueous ammonia solution (each time), dried over anhydrous sodium sulfate and evaporated to dryness. The obtained solid residue was washed with 20 ml of hexane and dried at a temperature of 40 ^° C., whereby 1.4 g (80%) of the product was obtained as a pale yellow solid, which was then purified by recrystallization from isopropanol.

Temperature 170 - 171 ^o C.

IR (KBr), cm ^-1 : 3360, 3040, 2779, 1485, 1315, 1152, 1124, 1092, 826, 801, 628, 533, 513.

NMR (CDCl ₃ ), ppm: 2.31 (singlet, 6H, N (CH ₃ ) ₂ ), 2.61 (singlet, 3H, CH ₃ -NH), 2.60-2.90 (multiplet, 4H, CH ₂ —CH ₂ —N), 2.80 (wide singlet, 1H, NH-SO ₂ ), 4.25 (singlet, 2H, SO ₂ —CH ₂ ), 7.00-7.50 (complex singlet, 4H, aromatic protons), 9.50 (broad singlet, 1H, NH indole).

Analysis: C ₁₄ H ₂₁ N ₃ O ₂ S (Molecular Weight 295.40).

Calculated,%: C 56.92, H 7.17, N 14.22, S 10.38
Found,%: C 56.88, H 7.20, N 14.19, S 10.80.

 Example 2. Decarboxylation with quinoline / diphenyl ether and copper dust.

2 g (6 mmol) of 2-carboxy-3- [2- (dimethylamino) ethyl] -N-methyl-IH-indole-5-methanesulfonamide was suspended in 20 ml of diphenyl ether, preheated to 50 ^° C. Then was added 1.4 ml (12 mm) of quinoline and 40 mg (0.6 mm) of copper dust and the stirred solution were heated to 205 ^° C. in a stream of dry nitrogen. The reaction mixture was maintained at this temperature until the evolution of CO ₂ ceased (1 h). After cooling to 50 ^° C., the reaction mixture was filtered through decalite. The filtrate was concentrated by distillation of the solvent in vacuo to give a residue, which was suspended in 40 ml of dichloromethane and then filtered. The new filtrate was washed three times with 15 ml of a 10% aqueous ammonia solution (each time), dried over anhydrous sodium sulfate and evaporated to dryness. The obtained solid residue was washed with 20 ml of hexane and dried at a temperature of 40 ^° C., whereby 1.2 g (69%) of the product was obtained as a pale yellow solid, and then purified by recrystallization from isopropanol. The physical and spectroscopic constants of this product are in agreement with the same constants of the product obtained in example I.

 Example 3. Succinate 3- [2- (dimethylamino) ethyl] -N-methyl-IH-indole-5-methanesulfonamide.

 2.95 g (10 mmol) of 3- [2- (dimethylamino) ethyl] -N-methyl-IH-indole-5-methanesulfonamide and 1.18 g (10 mmol) of succinic acid were mixed in 15 ml of distilled water for 10 min until complete dissolution is obtained. Succinate salt was isolated by removing water using known techniques such as vacuum stripping, freeze drying, spray drying, etc.

 The product can be purified by recrystallization from ethanol.

Temperature 164 - 154 ^o C.

IR (KBr), cm ^-1 : 3265, 3120, 1574, 1307, 1154, 1122, 821, 644, 528.

NMR (DMCO-d ₆ ), ppm: 2.36 (singlet, 4H, CH ₂ —COOH), 2.40 (singlet, 6H, N (CH ₃ ) ₂ ), 2.55 (singlet, 3H, CH ₃ -NH), 2.65-3.00 (m, 4H, CH ₂ -CH ₂ -N), 4.35 (singlet, 2H, CH ₂ -SO ₂ ), 6.85 (wide singlet, 3H , NH-DSO ₂ and COOH), 7.00-7.60 (complex singlet, 4H, aromatic protons), 11.80 (wide singlet, 1H, NH indole).

Analysis: C ₁₄ H ₂₁ N ₃ O ₂ S • C ₄ H ₆ O ₄ (molecular weight: 413, 29)
Calculated,%: C 52.29, H 6.58, N 10.16, S 7.75
Found,%: C 52.32, H 6.55, N 10.20 S 7.710

Claims (4)

1. The method of obtaining 3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide of the formula I

using a N-methyl-1H-indole-5-methanesulfonamide derivative in an organic solvent medium, characterized in that 2-carboxy-3- [2- (dimethylamino) is used as the N-methyl-1H-indole-5-methanesulfonamide derivative ethyl] -N-methyl-1H-indole-5-methanesulfonamide of the formula II

which is decarboxylated in the presence of a catalyst.  2. The method according to p. 1, characterized in that the decarboxylation of compound II is carried out in the presence of a solvent or mixture of organic solvents such as quinoline, or a mixture of quinoline and triethylene glycol dimethyl ether or diphenyl ether in the presence of quinoline in an inert atmosphere.  3. The method according to claim 1 or 2, characterized in that the decarboxylation of compound II is carried out in the presence of 5 to 10 mol.% Of a catalyst, such as copper dust, copper oxide (I), copper (I) chloride, copper chromite ( II), pentafluorophenyl copper or copper (II) salt of compound II, preferably copper oxide or copper dust. 4. The method according to claim 1 or 2, characterized in that the decarboxylation of compound II is carried out at 190 - 250 ^o C, preferably at about 205 ^o C.