SU461500A3 - The method of obtaining heterocyclic compounds - Google Patents

Description

(54) A METHOD FOR OBTAINING HETEROCYCLIC COMPOUNDS of the receptors in the presence of an acid binding agent with a compound of the formula 3 where R2 and Ra have the indicated meaning, and the gured irradiated compound of formula 1 is either isolated or converted into pharmacologically acceptable salts hydrogen is reacted with an alkyl halide of formula 4 Ri-Hal, where Rl is an alkyl group with 1-4 carbon atoms and Hal is bromine or iodine, in the presence of a strong base in an inert solvent or solvent mixture, after which it is isolated or converted into a salt and famous tricks. To carry out the proposed process, a reactive acid derivative is first prepared by reacting an acid of formula 2 with a chlorinating agent, such as thionyl chloride, phosgene, etc. Other reactive acid derivatives of formula 2 can be used, such as acid chloride hydrochloride, acid acid, mixed acid anhydrides of formula 2 with sulfuric or trifluoroacetic acid and others. For example, chloroform, methylene chloride, acetonitrile or dim are used as inert organic solvents. Ethyl formamide, as acid binding agents, are tertiary amines, for example pyridine or triethylamine. The reaction is carried out at temperatures from about -30 to -0 ° C. The compounds of formula 3 are added as a base, however, their salts can also be used. Alcoholates or alkali metal amides are preferably used as the strong base. In alkylation, preferably a suspension of an alkali metal alcoholate in liquid ammonia at -45 ° C introduces a compound of formula 1, where Ri is hydrogen, and after dissolving, the corresponding alkyl iodide in ether is added dropwise and transferred for approximately 1 hour at -40 ° C . A slurry of alkali metal alcoholate can also be prepared in situ by adding, in portions, to a solution of a lower aliphatic alcohol, such as methanol or ethanol, in liquid ammonia, metallic sodium or potassium until bleaching is achieved. For the alkylation reaction on 1 mole of the compound of the formula 1, about 2 to 5 moles of the alkali metal alcoholate and about the same excess of alkyl iodide are used. Example 1. N- (1-methyl-lilgil) -3-aminopyridine. To 150 ml of absolute dimethylformamide and 300 ml of absolute adonitrile at –30 ° C in the absence of moisture and in a stream of nitrogen, a solution of 8.55 ml (100 mmol) of oxalyl chloride in 60 ml of absolute acetonitrile is slowly added. After 5 minutes, at the same temperature and with stirring, 28.2 g (100 mmol) of water-free 1-methyl-melanic acid are added and transferred 30 minutes at - 10 ° C. The reaction mixture is then cooled to -30 ° C, 50 ml of absolute pyridine is added, and immediately after this, 14.1 g (150 mol) of 3-aminopyridine dissolved in 150 ml of dimethylformamide. The reaction mixture is poured after stirring for 2 hours at 0 ° C in 1 l of ice-cold soda solution (10%) and extracted with methylene chloride. After washing with water, the organic phase is dissolved over sodium sulfate, evaporated to a small volume and dried under high vacuum at 50 ° C. The raw product is chromatographed on a 50-cratia amount of basic alumina (activity P); the mso compound is removed with methylene chloride; M- (1-methyl-il-syl) -3-aminopyridine is eluted with methylene chloride and 0.5% methanol. Maleinate (from acetone); m.p. 176-178 ° C (decomposition); (afo 45 ± 2 ° C (with 0.5; pyridine). Analogously to Example 1, it is possible to prepare, starting from lysergic acid, the compounds listed in Table 1. Example 7. L-lysergyl-5-amino-2-chloropyridine. ; To a suspension of 3.25 g (10 mmol) of lyserglychloride hydrochloride in 100 ml of absolute methylene chloride in the absence of moisture at 0-5 ° C, a solution of 1.61 g (12.5 mmol) is added dropwise over about 15 minutes 5-amino-2-chloro-pyridine, 3.5 ml (25 mmol) of triethylamine and 50 ml of absolute methylene chloride. The reaction mixture is stirred at the same temperature for 40 minutes, then pouring ice and extract with methylene chloride and 2N soda solution while cooling with ice. The chloromethylene extract is washed with water, dried and evaporated. Hydromaleiate is obtained from the base of the silver powder by a known method Hydromaleicate from methanol; ); (a) o + 60 ° C (with 0.50; 50% ethanol). Example 8. H-lysergyl-5-amino-2-dimethylaminopyridine. Analogously to Example 7, reacting with 5- amino-2-dimethylaminopyridine basic compound, was obtained-hydromalo maleate, which is crystallized from methanol-ether; m.p. 174-177 ° C (decomposition); (a) about + 75 ° С (with 0.5; 50% ethanol). Analogously to example 1 or 7, other lysergic acid derivatives alkylated in position I can be obtained. Example 9. N- (1-methyl-lilgil) -3-aminopyridine.

461500

6 Table 1

To a suspension of 3.4 g (50 mmol) of sodium ethylate in 100 ml of liquid ammonia, 3.44 g (10 mmol) of N-lysergyl-3-aminopyridine are added in portions at -45 ° C. After stirring for 15 minutes at -45 ° C, a solution of 7.1 g (50 mmol) of methyl iodide in 5 ml of ether is slowly added dropwise and stirred for 1 hour at -40 ° C. For processing, it is poured into 300 ml of methyl chloride cooled to -40 ° C and about 200 ml of cold ice-saturated bicarbonate are added with stirring

Example

Compound

K- (1-methyllylgil) -5-amino-2chlorpyridine as hydrochloride (from acetone-ether)

K- (1-methyl-lilgil) -5-amino-2dimethylaminopyridine as dihydrochloride (from methanol-ether)

K- (1-methyl-lilgil) -5-amino-2k-butoxypyridine in the form of hydromaleicate (from methanol-acetone)

K- (1-methyllylgil) -3-amino-2b-dimethoxypyridine as hydrotartrate (from acetone-ether)

M- (1-methyllylgil) -5- (M-methylamino) -2-methoxypyridine as hydrochloride (from methanol-acetone)

N- (1-methyl-lilgil) -5-amino-2methoxypyridine in the form of tartrate (from methanol-ether)

on three . The aqueous phase is further extracted with methylene chloride, the combined organic phases are dried over sodium sulfate and evaporated in vacuo at 40 ° C. From the obtained base powder in a known manner, maleate of the compound is obtained.

Maleinate (from acetone); m.p. 176-178 ° C (decomposition); (a) D -45 ± 2 ° С (s 0.5; pyridine).

Analogously to example 9, you can get, on the basis of the corresponding compounds, the substances listed in table. 2

table 2

Specific rotation,

Melting point, ° C deg.

(a) (, 5; 50% ethanol)

(but)

(, 5; ethanol)

(") L +52 (, 5; 50% ethanol)

(a) (, 5; 50% ethanol)

(but)

(, 5; 50% ethanol)

(, 5; pyridine)

PRE D SM UET of Invention

The method of obtaining heterocyclic compounds of formula 1

-R 2

, CO-NT C

.M-SNZ

CJ

where RI is a hydrogen atom or an alkyl group with 1-4 carbon atoms;

R2 is hydrogen or an alkyl group with 1--4 carbon atoms;

Cs is a 3-pyridyl residue that can be optionally substituted with one or more alkyl residues with 1-4 carbon atoms, an alkoxy group with 1-4 carbon atoms, a hydroxyl group, a halogen or an amino, alkylamino or dialkylamino group (each with alkyl containing 1--4 carbon atoms), or their salts,

characterized in that the reactive derivative of the heterocyclic acid of formula 2, for example the hydrochloride chloride.

Hhun

, N-CH3

but)

where RI has the specified value

reacted in an inert organic solvent or in a mixture of solvents in the presence of an acid binding agent with a compound of formula 3

Ds

HN:

(3)

U,

where Kg and Nz have the specified value,

and the compound thus obtained

Formulas 1 are either isolated or translated into

salts, or in the case when Ri is hydrogen,

subjected to interaction with the alkyl halide of formula 4

RI - Hal, (4)

where Rl is an alkyl group with 1-4 carbon atoms and Hal is bromine or iodine, in the presence of a strong base in an inert solvent or mixture of solvents, after which it is isolated or converted into salts by known methods.

Convention priority on the grounds:

10.12.71 (Application No. 18051/71) - on the basis of obtaining amides of formula 1, where Ri is an alkyl group, from an acid of formula 2 and an amine of formula 3;

10.12.71 (Application No. 18052/71) - on the basis of alkylation of compounds of formula 1, where RI is a hydrogen atom, with an alkyl halide of formula IV.