SU795455A3 - Method of preparing gamma-(sec-amino)-o-aminobutyrophenone derivatives or their salts - Google Patents

Abstract

PURPOSE:0-Amino butyro-phenone derivatives useful as psycotropic drugs such as tranquilizers, etc. are efficiently prepared in high purity.

Description

(5d4) METHOD FOR OBTAINING DERIVATIVES

jf- (VTOR. -AMINO) -O-AMINOBUTIROPHENON OR THEIR SALTS

one

The invention relates to an improved process for the preparation of V - (sec. Amino) -o-aminobutyr6-Phenone derivatives of the general formula

ABOUT

II

s-Ch ONGNg-g, Shg (I)

where R is hydrogen or fluorine;

2 - secondary amino group or a group corresponding to one of the formulas

one

-sh

A1

but

 - "CXi

ABOUT

where. is phenyl substituted by a halogen, methyl, methoxy or trifluoromethyl group; R-I is hydrogen or hydroxy, hydrogen or halo;

RA is hydrogen or methoxy group, or their salts, possessing biological activity.

In the patent and technical literature describes how to obtain

Y-V-amino-o-aminobutyrophenones, which includes the steps of nitration and p-fluorotoluene, oxidation, cyclization, alkylation, amination and decyclization 1.

On the technical side, the proposed method is a method of producing y-second-amino-o-amine-butyrophenones, consisting in the sequential alkylation of m-difluorobenzene, amination, benzylamination, and hydrolysis 2, the availability of m-difluorobenzene is low with m-difluorobenzene and hydrolysis. thorough purification at the benzylamine stage and, as a result, a decrease in the yield of the target product. The aim of the invention is to eliminate the indicated disadvantages and to simplify the process. The goal is achieved t & that the compound of the general formula C-ftlaCHgdHzZ where W is oxygen, ethylenedioxy or ethylene thiol group; R and Z have the above values, undergoes the formation of iron or its salt in the presence of acid or by treatment with hydrogen in the presence of palladium on activated carbon, and in the case when W means ethylenedioxy or ethylene thio group, the resulting reduction product is subjected to hydrolysis. The reduction is preferably carried out in an inert solvent, for example, water, an alcohol (for example, methanol, ethanol, propanol), an aromatic hydrocarbon (for example, benzene, toluene), a ketone (for example acetone, methyl ethyl ketone) or an ether (for example, tetrahydrofuran, dioxane) . The hydrogenation is preferably carried out in the presence of palladium on activated carbon in the alkanol. In most cases, the reaction readily proceeds at room temperature and at atmospheric pressure of hydrogen. Upon reduction of the ketal, - ((Vttamino) -o-aminobutyrophenone and / or its ketal is obtained, depending on the reaction conditions. Upon receipt, the ketal is converted to the corresponding 2 (sec. -Amino) -o-aminobutyrophenone by hydrolysis. ..- amino) -o-aminobutyrone non and / or its ketal is recovered from the reaction mixture by known methods of isolation and purification in free form or in the form of their salts, Example 1. A mixture of 4.9 g of hydrochloride of -I 4-oxy- 4- (3-trifopormethyl phenyl) -piperidino-D-4-fluoro-2-nitro tyrofenone, 1 g of 5% palladium on activated carbon (50% moisture) and 80 g of methanol are vigorously stirred in a hydrogen atmosphere at room temperature before absorbing the calculated amount of hydrogen. The catalyst is filtered off, washed with hot metal, and the filtrate is evaporated in vacuo. The solid obtained in the residue was washed with isopropanol, filtered off, washed with dizopropyl ether. 3.9 g of monohydrochloride Y-p-hydroxy-4- (3-trifluoromethylphenyl) -piperidine-2-amino-4-fluorobutyrrphenone are obtained, m.p. 202-204c. The free base is obtained by known methods. Its melting point is 106-107 s (recrystallization of toluene). PRI mme R 2. A mixture of 6.42 g of 4- 4-hydroxy-4- (3-trifluoromethylphenyl) -piperidino - - (4-fluoro-2-nitrophenyl) -1,1-ethylenedioxy-n. Butane, 20 g of water, 80 g of ethanol and 1.4 g of concentrated hydrochloric acid are heated to 70 s. Then 6.7 g of iron powder (dust) are introduced into it in portions and gently heated for 1 hour at boiling point. The precipitate is filtered off, washed with hot ethanol, and the filtrate is evaporated in vacuo. The residue is alkalinized with a 10% aqueous solution of sodium hydroxide and the whole mass is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulphate and evaporated under vacuum. The residue is dissolved in 25 g of isopropanol and, upon cooling, 5 g of concentrated hydrochloric acid are poured. The precipitated crystals are filtered, washed with toluene, dried, and 4.4 g (yield 80%) are obtained, monohydrochloride in y — 4-hydroxy-4- (3-trifluoromethylphenyl) -piperidine -2-amine-4-fluorobutyrophenone, mp. 208.5209, 5 ° C. PRI-m e 3. Replacing in the example. 2 4 - 4-OXI-4- (3-trifluoromethylphenyl) -piperidines-1- (4-fluoro-2-nitrophenyl) -1,1-ethylenedioxy-n-butane per hydrochloride) f-4-hydroxy-4 - ( 3-methylphenyl-piperidino-D-4-fluoro-2-nitrobutyrophenone 3 trifluoro get the same compound. Example 4. The following o-aminobutyrophenones are prepared in the same way as described in Example 1 or 2: Hydrochloride g (4-chlorophenyl) -4-oxypiperidine-J-2- amino-4-fluorobutyrophenone, mp (decomp.); y - | 4- (4-chloro-3-trifluoromethylphenyl) -4-hydroxypiperidino -2-amino-4-fluorobutyrophenone, mp 166-167C; hydrochloride - 4- (3, 4-dichlorophenyl) -4-rxipiperidino -2-amino-4fluorobutyrophenone, etc. 214-214, 5С; hydrochloride of (3-chloro-4-methylphenyl) -piperidinoT-2-amino-4fluorobutyrophenone, mp 207-120С; hydrochloride - (4-phenylpiperidino) -2-amino-4- fluorobutyrophenone, mp approx. y - (4-oxo-1-phenyl-1,3,8-triazaspiro; -4.5-decan-8-yl) -2-amino-4fluorob tirofenone, mp 198 ° C; 2 (2-oxo ..- 1-benzimidazolinyl) -piperidino-D-2-amino-4-fluorobutyrophenone, mp 230-235:;

hydrochloride g-G4- (4-chlorobenzyl) -4-hydroxypiperidino-D-2-amino-4-fluorobutyrophenJa, so pl. (times ..);

Y - | 4- (2-methoxyphenyl) -piperazino -2-amino-4-fluorobutyrophenone, m.p. 83-87 ° C;

y is G4-hydroxy-4- (4-methylphenyl) -piperidino1-2-amino-4-fluorobutyrophenone, m.p. 140 ° G;

g - (4-benzyl-4-hydroxypiperidino) -2-aminobutyrophenone, m.p.

(4-chlorobenzyl) -4-hydroxypiperidino -2-aminobutyrophenone, m.p.

Tf - (4-oxo-1-phenyl-1, 3.8-triazaspiro-, 5-decan-8 -yl -2-aminobutyrophenone, mp. Other.,

Claims (1)

Invention Formula one . The method of obtaining derivatives of U - (sec.-Amino) -o-aminobutyrophenone of the general formula ABOUT (- (H2 (1H2 (H2-2; R (one) NHo where R is hydrogen or fluorine; Z is the group of the secondary amine, or the group corresponding to one of the formulas: jj.  : ; --CAJ KP.-NGU U where AP is phenyl having the substituents are halogen, methyl methoxy or trifluoromethyl group; R is hydrogen or hydroxy; R is hydrogen or halo; R 3 is hydrogen or methoxy, or a salt thereof, different; In order to simplify the process, the compound of formula i W // (J- (H2 (, Jfog 25 where W is oxygen, ethylenedioxy or ethylene thiol group; R and 2 have the above values, are reduced by iron or its salt in the presence of acid or by treatment with hydrogen in the presence of palladium on activated carbon, and in the case that the ethylenedioxy or ethylenedithio group, the resulting reduction product is subjected to hydrolysis. Sources of information taken into account in the examination 4Q 1. Belgium patent 796893, cl. C 07 Oh, publish.1973. 2, Belgium Patent 753472, cl. Since 07 Oh, publish.1970.