SU539520A3 - The method of obtaining pyrrolyl compounds or their salts - Google Patents

Description

(54) METHOD FOR OBTAINING PYRROLYL COMPOUNDS OR THEIR SALTS

one

This invention relates to a process for the preparation of novel pyrrolyl compounds which can be used in the pharmaceutical industry.

A known method for the preparation of hydroxyamines by the interaction of epoxy compounds or hydrohalides with amines.

The use of the known method for the production of (pyrrolyl-1) -phenoxypropanol made it possible to obtain new derivatives of 1- (epirrol-1-phenoxy) -3-aminopro-2-nola-2, possessing valuable pharmacological properties.

According to the invention, a method is provided for the preparation of pyrrolyl compounds of general formula I

R

O-CH Mr. SNON-CH, -NH-R

where R is lower alkyl containing up to seven carbon atoms, or a residue.

-NI - N-morpholino,

RI and - hydrogen or lower alkyl containing up to four carbon atoms, or their salts, meaning that a compound of the general formula II

k, k,

X

ll

ten

O-SNG-CH-SNG-Z

where RI and R2 have the indicated values, X and Z together form an epoxy group or X - oxygen, and Z - halogen, is reacted with an amine of the general formula KMI, where R has the indicated value, or with morpholine, the resulting racemate is divided, if necessary, into the optical antipodes and the target product are isolated in the form of the centering of the pl or salt.

In compounds of general formula I, the radical

R is lower alkyl containing up to seven carbon atoms, it can

be unbranched or branched and attached in any position with butyl, amyl, hexyl or heptyl, in particular n-pronyl, ethyl, first of all methyl, isopropyl or tert-butyl. Lower alkyl RI and / or R2 is primarily methyl. The reaction is carried out in a well-known manner. When using a compound of formula II, where Z is halogen, the starting material is usually reacted in the presence of the main condensing agent and / or with an excess of amine. Suitable basic condensing agents are, for example, alkali metal hydroxides, such as sodium or potassium hydroxide, alkali metal carbonates and alkali metal alkoxides, such as sodium methoxide, potassium thiatlate, and potassium heated. Potassium. The desired products are isolated in free form or in the form of salts. So, you can get basic, neutral or mixed salts, in the appropriate case, their hemi-, mono-, sesquiiln polyhydrates. Salts of the compounds obtained can be converted by known methods to the free base, for example, when using fixed assets such as alkali or ion exchangers. On the other hand, the resulting free bases can form salts with organic or inorganic acids. For the preparation of salts, acids such as, for example, hydrogen halide, sulfuric, phosphoric, nitric, perchloric, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, for example, formic, acetic, iropionic, succinic, sulfuric, acetic, acetic, iropionic, succinic, sulfuric, acetic, acetic, iropionic, succinic, sulfuric, or lactic acids, for example, formic, acetic, iropionic, succinic, sulfuric, acetic, acetic, iropionic, succinic, or sulphonic acids, for example formic, acetic, iropionic, succinic, sulfuric, acetic, acetic, iropionic, succinic, or sulphonic acids, such as formic, acetic, iropionic, succinic, sulfuric, acetic, acetic, iropionic, succinic, sulfuric, or lactic, are used to obtain salts. citric, ascorbic, maleic, hydroxymaleic, pyruvic, fumaric, benzoic, anthranilic, d-hydroxybenzoic, salicylic, methane, ethane, cyclohexane, hydroxyethane, ethylene sulfonic acid; halobenzene-, toluene-, naphthalenesulfonic acid or sulfanilic acid; methionine, tryptophan, lysine or arginine. These and other salts of pyrrolyl compounds, for example picrates, can also serve for the purification of the resulting free bases. The free base is then converted to salt, which is separated and the base is again freed from the salt. The proposed compounds may exist depending on the starting materials used in the form of optical antipodes or racemates. The resulting isomeric mixtures can be divided into two pure geometric isomers, for example, by chromatography or by using a complexing compound of a heavy metal, for example a silver compound, pretreated silica gel or alumina, or by forming a compound of a heavy metal, for example silver nitrate complex, to separate it. isomers, for example, by fractional crystallization and subsequent release of pure isomers. Racemates can be separated by known methods on antipodes by exposure to suitable means, for example, by recrystallization from an optically active solvent, using microorganisms or by reacting with an optically active acid, forming salts with different racemates with different solubility. Especially widely used optically active acids are the D- and L-forms of tartaric, di-o-toluene, block, almond, camphorsulfuric or quinic acid. Preferably, the L-antipode is isolated. The starting compounds of the formula P are obtained by a known method, for example, from phenol OH or from its phenol and epichlorohydrin. By reacting the epoxide of formula II thus obtained with concentrated hydrochloric acid, the corresponding chlorohydrin of formula II can be obtained. Example 1. 10 g (0.047 mol) of 1- 4-pyrrolyl- (1) -phenoxy-2,3-epoxypropane are dissolved in 100 ml of iso-pyro-iol, 4.25 ml (0.05 mol) of isopropylamine are added and the mixture is boiled 3 hour with reflux. The reaction mixture is evaporated in vacuo and the resulting crude base is recrystallized from ethyl acetate. 1-4-pyrrolyl- (1) phenoxy -2-hydroxy-3-isopropylaminopropane is obtained; its hydrochloride, obtained from a methanolic solution of the base with a solution of hydrogen chloride in ether, has a melting point of 200 ml. 208-210 ° C. The source material can be obtained as follows. 5.0 g (31.4 mmol) of 4-pyrrolyl- (1) -feiol are heated with 11.6 g (9.9 ml) of epichlorohydrin and 0.1 ml of piperidine for 6 hours under reflux. Instead of piperidine, a small amount of potassium carbonate and acetonitrile can be used. The excess epichlorohydrin is distilled off and the residue is distilled at 160 ° C and 0.05 mm Hg. Art. The resulting 1-4-pyrrolyl- (1) phenoxy -2, 3-eioxypropane can be used without further purification. The 4-pyrrolyl- (1) -phenol used can be obtained from p-aminophenol and 2,5-dimethoxytetrahydrofuran in glacial acetic acid. Output 9.9 g, 78% of theory. Example 2. To a solution of 26.9 g (pyrrolyl-1) of phenoxy -2,3-epoxypropane in 250 ml of isopropanol was added 52 ml of tert-butylamine and refluxed for 1.5 hours. The oil remaining after evaporation of the volatile components in vacuo is distilled under high vacuum to give 1-treg-butylamino-3-o- (pyrrolyl-1) -phenoxy -2-propanol as a colorless oil with m.p. 130-140 ° C (0.04 mm Hg. Art.). It forms with fumaric acid a neutral fumarate with m. Pl. 203-204 ° С (from methanol). The starting material can be obtained as follows.