SU457211A3 - The method of obtaining derivatives of 1-phenoxy-3-aminopropan-2-ol - Google Patents

Description

one

The invention relates to a process for the preparation of new amino alcohols not described in the literature, in particular 1-phenoxy-3-aminopropanols, which have pharmacological activity and can therefore be used in medicine.

A known method of producing amino alcohols of the general formula

 HE

one

// - 0-CH2-CH-CH2-NH0-CH2-CH CH2

in that connection is common

Y x 0-CHrCiH-CH2 0-CH2-CiH CH2

subjected to interaction with isopropylamine in an inert solvent, for example alcohol.

However, in the literature there are no details on the preparation of 1-phenox-3-aminopropan-2-ol derivatives of general formula 1

yo- H2-CH-dH2-NH-x it

where X is a group

-ffi CH-C-Q

about

or

20

-sng-t he

N-up to 6 carbon atoms, cycloalkyl or cycloalkenyl with 5-8 carbon atoms, alkoxy, alkenyloxy or alkynyloxy, containing up to 5 carbon atoms, phenyl, chlorine or bromine or group-NRiR2, where is alkyl with 1-4 carbon atoms or acyl containing up to 11 carbon atoms; R2 is hydrogen or alkyl containing up to 4 carbon atoms, possessing chain properties and therefore can be used in medicine. A process for the preparation of 1-phenoxy-3-aminopropan-2-ol derivatives of the general formula 1, or their salts is described, which consists in that the compound of the general formula 2 / UH-CH2-CH-CH2-CH2 is reacted with a compound of the general formula 3 YX where X is as defined above; Y is halogen, and if X is a group of formula a, then Y is OH, -OK, or -ONa. The core of phenyl 1 is predominantly substituted with vinyl, allyl, metal, crotyl, diclopentenyl, cyclopentyl, cyclohexyl or methoxy, ethoxy, propoxy, butoxy, allyloxy, metaloxy, or propargyloxy, or NRiRa, where RI is , methyl, ethyl, acetyl or benzoyl, Ra - methyl or ethyl. The pyridine ring in compounds of formula 1 can be substituted in any position (2-, 3- or 4-position). This reaction is preferably carried out in a suitable solvent or dispersant, such as benzene, toluene, acetone or dioxane. Polar solvents, in particular alcohols, are preferably used as solvents. The reaction is preferably carried out at normal temperature. In the event that X is a group of formula a, the reaction is accelerated by the addition of an acid, preferably hydrochloric. If, then catalytic amounts of an acid, such as acetic or formic acid, are already sufficient. If Y-ONa or OK, about 1 mole of acid is added. It is also possible to use the compound of general formula 2 as a salt. , Derivatives of amino alcohols of general formula 1 can be oxazolidines of the general form iVo-dnA / x, Kz formed by condensation of compounds of general formula 1 with an aldehyde of the formula Rs-CHO, where Rs is hydrogen or a lower alkyl residue containing up to 4 carbon atoms, X has the above values . The desired product is isolated by known methods in free form or in the form of a salt, in the form of a racemate or an optically active antipode. For the salts of the compounds of general formula 1, inorganic and organic acids are used, preferably hydrochloric or hydrobromic, phosphoric, sulfuric, oxalic, lactic, tartaric, acetic, salicylic, benzoic, citric or adipic acid. From the racemates, optically active compounds can be obtained by a well-known method by splitting the racemates by treating with optically active acids, for example + mandelic, tartaric, + dibenzoyl tartaric, - di-and-toluene and + camphoric acid. When a racemate is reacted with an optically active acid, salts are obtained that differ in optical and other physical properties, such as solubility and melting point, and which can therefore be separated, for example, by fractional crystallization. From the salts thus separated, it is possible to release the optically active compounds of the general formula by treating with bases, for example, potassium hydroxide or sodium hydroxide. The examples describe how to get the case: the out and the starting products. Example 1. 4.2 g of 1-amino-3- (o-allyloxyphenoxy) propan-2-ol-hydrochloride are suspended in 33 ml of alcohol, then 2.8 g of nicotinoyl vinyl alcohol sodium salt is added and the mixture is stirred for 20 hours at room temperature. The suspension is sucked off and the residue is washed with alcohol. The filtrate, along with the wash alcohol, is evaporated in vacuo. An oily product is obtained which solidifies after some time. It is treated several times with water and then recrystallized from alcohol. Thus, 4.6 g (81%) of 1-nicotinoylvinylamino-3 - (o - allyloxyphenoxy) -propan-2-ol are obtained, m.p. 98 ° C. Calculated,%: C 67.8; H 6.2; N 7.9. C2H22N2O4. Found,%: C 67.7; H 6.4; N 8.1. The initial sodium salt of nicotinoylvinyl alcohol is obtained as follows. 47 g of sodium methoxide are suspended in 340 absolute benzene, then a mixture of 74 g of formic acid ethyl ester and 100 g of 3-acetylpyridine is slowly added dropwise while moving and 10 ° C. The mixture is kept for 24 hours at room temperature: 2 times with absolute benzene, 2 times with absolute alcohol and 2 times with ether. In this way, sodium oligo nicotinoyl vinyl alcohol is obtained (yield 90% of theoretically possible).

If used instead of 3-acetylpyridine 2 or 4-acetylpyridine, then the sodium salt of vinylene pyridine-2 or 4-carboxylic acid is similarly obtained by reacting with formic acid ester and sodium methoxide.

The starting 1-amino-3- (o-allyloxyphenoxy) propan-2-ol was prepared as follows.

60 g of 1- (o-allyloxyphenoxy) -2,3-epoxypropane, obtained from o-allyloxyphenol and epichlorohydrin in the presence of potash in acetone, is dissolved in 600 ml of methanol, 300 ml of liquid ammonia are added and stirred for 3 hours in an autoclave . It is then evaporated, the residue is dissolved in benzene, extracted 2 times with dilute hydrochloric acid, the aqueous acidic phase is separated, made basic, 3 times extracted with benzene and the combined benzene phases are evaporated. The solid residue is recrystallized 1 time from benzene. In this manner, 1-amino-3- (o-allyloxyphenoxy) propan-2-ol is obtained. (Yield 67% of theoretically possible), so pl. 89 ° C.

The base can be converted to 1-amino-3 (o-allyloxyphenoxy) propane – 2-ol-hydrochloride (mp. 110 ° C) by treating hydrochloric acid in ether.

Example 2. 4.4 g of 1-amino-3- (g-t / er-butnlfeioxy) -propan-2-ol are dissolved in 80 ml of acetic acid ester and 5.6 g of anhydrous potash are added. While cooling and stirring, a mixture of 4.1 g of nicotinoyl vinyl chloride-hydrochloride (obtained from the sodium salt of nicotinoyl vinyl chloride:} alcohol, which was first converted by treatment with HCl gas into free nicotinoyl vinyl alcohol hydrochloride and then treated with thionyl chloride, was slowly added to this mixture. vinylene chloride - nicotinic acid hydrochloride) in 50 ml of acetic acid ester and then stirred for 24 hours at room temperature. Then it is filtered off with suction, the residue is dissolved in water, alkalized with sodium bicarbonate and the solution is extracted again with acetic acid ester. The acetic acid ester extracts are evaporated in vacuo along with the first acetic acid ester filtrate. After repeated recrystallization from toluene, 5.8 g (82% of the theoretically possible) 1-nicotinoylvinylamino-3 (/ g-treg-butylphenoxy) -propan-2-ol, m.p. 97 ° C.

Calculated,%: C 71.2; H 7.3; N 7.9.

C2lH26N2O.4.

Found,%: C 72.1; H 7.3; N 7.7.

1-Nicotinoylvinylamino-3 - (p-treg-butylphenoxy) -propan-2-ol can, as described in Example 2, be reduced with sodium borohydride to 1 - (3p-pyridine-3-oxypropylamino) -3- (pgret- butylphenoxy) propan-2-ol. (mp pl. dioxalate 176 ° C).

Example 3. 11.4 g of sodium salt of vinylene pyridine-4-carboxylic acid and 16.5 g of 1-amino 3- (o-ethoxyphenoxy) -propan-2-ol-hydrochloride are dissolved in 120 ml of ethanol for 24 hours at room temperature, temperature Suction is carried out, the residue is washed with ethanol, and the ethanol filtrates are then evaporated in vacuo. An oily product is obtained which solidifies after several hours. The product is washed several times with water, then it is recrystallized from menthol - water. Thus, 15 g (66% of theoretically possible) of 1-isonicotinoylvinylamino-3-Cc-ethoxyphenoxy) propan-2-ol are obtained, m.p. 69 ° C.

Calculated,%: C 66.6; H 6.4; N 8.2.

CloH22N204.

Found,%: C 66.3; H 6.6; N 7.9.

Corresponding to examples 1-3, the compounds listed below are obtained. 2-Py- means 2-pyridyl; 3Ru-3-pyridyl residue and 4-Py-4-pyridyl residue, respectively.

In the following, its table shows the compounds of the general formula

O-CH-CH-bNg-HH-X. HE

and

457211

12

a continuation

The subject of the invention. A method for producing 1-phenoxy 3-aminopropan-2-ol derivatives of the general formula I {l O-CHi-CH-CHg-1 JH-X where X is the group --CH-CH-C II o -dHj-CHfCH phenyl 1 can be substituted by one two or three times alkyl with 1-4 carbon atoms, alkenyl or alkynyl containing up to 6 carbon atoms, cycloalkyl or cycloalkenne with 5-8 carbon atoms with alkoxy, alkenyloxyla or alkynyloxy, containing up to 5 carbon atoms, phenyl, chlorine or bromine, or the group -NRiR2, where RI is alkyl with 1-4 carbon atoms or acyl containing up to 11 carbon atoms; RS is hydrogen or alkyl containing up to 4 carbon atoms, or salts thereof, characterized in that the compound of the general formula 2 V O-CH2-CH-CH i:, OH is reacted with the compound of the general formula 3 where X has the indicated values, Y - halogen, and in the case of, if X is a group of the formula a, then Y-OH, -OK or -ONa, followed by separation of the target product in a known manner. Priority signs: 03.08.71-pyridine ring is substituted in the 3-position; 02.22.72 - the pyridine ring is substituted in the 2- or 4-position.