SU447887A1 - Method for producing 1,3,3-trisubstituted 3-azolylpropines - Google Patents

Description

one

The invention relates to a process for the preparation of novel 1,3,3-trisubstituted Z-azolylpropines, as well as their salts, which have high activity against fungi and yeast, which are pathogenic to humans and animals, and can be used in the pharmaceutical industry.

A known method for the preparation of imidazole derivatives is that the oxo compound is reacted with thionyl bis-imidazole.

A method is proposed for the preparation of new 1,3,3-substituted 3-azolyl props of the general formula 1

. V (1)

H C C-Ag

BUT

where R1 is hydrogen, chlorine, bromine or iodine;

W is an alkyl group, a cycloalkyl group which is substituted if necessary, or an aryl group which is substituted if necessary;

R R and R are the same or different, denote hydrogen, alkyl, alkoxy or alkyl mercapto group, as well as electronegative substituents;

AZ is a nitrogen-containing five-membered heterocyclic radical, if necessary, as well as their salts. Alkyl groups (R) usually contain

1-6, preferably 1-4 carbon atoms. They may be unbranched or branched and contain double or triple bond. Especially preferred radicals are methyl, ethyl, “-propyl, isopropyl radicals, and also n-, iso- and tert-butyl radical.

Cycloalkyl groups (R) usually consist of 3-7, preferably 5 or 6 carbon atoms. They may contain one or

several, preferably one, double bond and, as a substituent, one or several, preferably one, of the ori R R and R radicals indicated.

Substituted, if necessary, aryl groups (R) usually contain 6-10 carbon atoms in the aryl part and may be substituted by one or more, preferably one or two, indicated at R-

R and R radicals. As the preferred aromatic radical R, a phenyl radical is used, in particular an unsubstituted or substituted chlorine or bromine atom or a nitro group or a methyl group, a phenyl radical.

Alkyl, alkoxy and alkyl mercapto groups (R 3, R 4 and R) preferably contain 1-4, in particular 1 carbon atoms. The alkyl groups or alkyl components of these radicals may be unbranched or branched and contain a double or triple bond.

Examples of electronegative substituents (R, RR) include halogens such as fluorine, chlorine, bromine and iodine, preferably chlorine and bromine, nitro and haloalkyl groups, preferably with 1-4 carbon atoms, especially 1 or 2, and preferably 1-5 halogen atoms (fluorine, chlorine and bromine), in particular the trifluoromethyl group, the pian group, and the alkylsulfinyl and alkylsulfonyl group, the alkyl components of these radicals being 1-6 carbon atoms, preferably 1-4 carbon atoms and may be undeveloped IMPLEMENT or branched, saturated or unsaturated.

Especially preferred substituents are {R R R) -hydrogen and chlorine, as well as a nitro and methyl group.

As optionally substituted nitrogen-containing five-membered heterocyclic radicals (Az), the imidazolyl, pyrazolyl 1,2,4-triazolyl and 1,3,4-triazolyl radicals, especially radicals, which have the following formulas, can be preferably substituted.

I n

N

N

L N | 7, ь

I

N

"WG"

Nn

where R, R, which may be the same or different, mean hydrogen or lower alkyl radicals with 1-4 carbon atoms, preferably with 1 carbon atom.

A particularly preferred radical (Az) is the unsubstituted imidazolyl and unsubstituted 1,2,4-triazolyl radical.

As salts of the compounds of formula 1, salts with acids are preferred. Examples of such acids are hydrohalic acids, in particular hydrochloric and hydrobromic acids, phosphoric acids.

mono- and bifunctional carboxylic acids, such as acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid, lactic acid, and 1,5-naphthalene disulfonic acid.

Especially preferred are new compounds of general formula a

(la)

where R1 is hydrogen;

 - alkyl radical with the number of carbon atoms of 1-3 or substituted if necessary by chlorine, nitro or methyl group f. the fepyl radical,

and their salts.

The method of obtaining the target compounds of general formula 1 is that the compound of general formula 2

(2) -C C-C-L2

AT 2

where R2, R, R R5 and Az have the indicated meanings, and M is an atom of an alkali metal such as lithium, sodium or potassium, or a radical of 5 mm of log magni of the formula Z-Mg, where Z is a halogen atom of chlorine, bromine or iodine ,

subjected to interaction with the acid of the General formula 3

02-OH (3)

where Z has the specified value in the presence of a solvent at a temperature of approximately O-120 ° C,

with the subsequent isolation of target compounds by known methods in free form or in the form of salts.

The reaction should be carried out in the environment

polar solvents. As an example

can be called water, pyridine, lower alcohols

0 (preferably with carbon number

1-4), for example methanol and ethanol or mixtures

these solvents. Compounds of Formula 2

reacted with subhalogenic acids of formula 3, preferably

in molar amounts.

Example 1. 1-Bromo-3,3-diphenyl-3-imidazolyl- (I) - (Pronin.

-iJ

Br-C C-C-N

(four)

A solution of 2.75 ml (55 mmol) of bromine in 37.5 ml of 12% caustic soda at room temperature for 20 min is added dropwise with a solution of 12.9 g (50 mmol) of 3.3 -diphenyl-1-imidazolyl- (1) propyne in 50 ml of pyridine. At the same time, the reaction mixture is heated to 40 ° C, cooled to 20 ° C, after 3 hours, poured into 1000 ml of water, and the precipitated K is sucked off. For a solution of 12.9 g (50 mmol) of 3,3-diphenyl-3 imidazolyl- (1) -: propyne in 100 ml of methanol at a temperature between 20 and 30 ° C, 25 ml of 10 n are added dropwise. caustic soda solution and at the same time, 12.7 g (50 mmol) of iodine are simultaneously added in portions. Stir further for 1 hour at room temperature, suck the crystalline precipitate and stir at 25-30 ° C with 60 ml of acetonitrile. Thus, 15.6 g (81% of theory) of 1-iodo-3,3-diphenyl-imidazolyl- (1) -propyne with m.p. 198-199 ° C (decomposition). The subject matter of the invention is 1. Method for producing 1,3,3-trisubstituted 3-azolyl propions of the general formula 1: R-C, C-C-Az: 1 where R is hydrogen, chlorine, bromine or iodine; R2 is an alkyl group, a cycloalkyl group which is optionally substituted or an arnl group which is substituted if necessary; R, R and R, which may be the same or different, mean hydrogen, mixed with 60 ml of acetonitrile at 25-ZO C, the residue is sucked off and washed with ether. Thus, 13.3 g (79% of theory) of 1-bromo-3,3-dpphenyl-3-imidazolyl- (1) -propin with m.p. 186.5-187 ° C.

Example 2. 1-Iodine-3,3-diphenyl-3-imidazolyl- (1) -propin. d is alkyl, alkoxy or alkyl mercapto, as well as electronegative substituents. AZ is a nitrogen-containing, five-membered heterocyclic radical, if necessary, as well as their salts, characterized in that the compound of the general formula 2 wherein RR RS R and Az have the indicated value, and M denotes an alkali metal atom such as lithium, sodium or potassium, or a halomagnesium radical of the formula Z-Mg, where Z is a halogen atom, such as chlorine, bromine or iodine, is reacted with an acid of the general formula 3 Z -OH, (3) where Z has the indicated meaning, followed by isolation of the target compounds by known methods. 2. A method according to claim 1, characterized in that the reaction is carried out in an environment of polar solvents at a temperature of approximately O-120 ° C.