CS260090B1 - Method of methoxyphenoxy acetic acids' new amides and hydrazides preparation - Google Patents

Description

The invention relates to a process for the preparation of novel amides and hydrazides of methoxyphenoxyacetic acids of general formula (I)

R

CH ₃ O

OCHjCONHR ¹ (I),

R wherein R is hydrogen or methoxy and R ² is 2-phenylethyl, isopropylamino, piperidino or morpholino.

The compounds of formula (I) according to the invention are intermediates for the synthesis of pharmacodynamically active compounds useful in practice as pharmaceuticals. Some of them have biological effects on their own. For example, N- (2-phenylethyl) -4-methoxyphenoxyacetamide, which is very toxic (acute toxicity in mice by oral administration of LDjq is greater than 2,500 mg / kg). At oral doses higher than 300 mg / kg, the substance suppresses spontaneous motility in mice, i.e. acts centrally depressing. At oral doses of 100-300 mg / kg, it significantly inhibits reserpine-induced ptosis in mice. Thus, it has an antireserpine effect, which is an indicator of the antidepressant effect in patients. At a concentration of 50 µg / ml, it inhibits the growth of Mycobacteria tuberculosis in an in vitro assay. It also has a clearly indicated anthelmintic effect on the tapeworm Hymenolepis nana. Another compound of the invention, i.e. 1- (3,4,5-trimethoxyphenoxyacetyl) -2- (2-propyl) hydrazine, is also of low toxicity in mice; LD ≥ _Q = 500 mg / kg iv At an intravenous dose of 100 mg / kg, it causes profound blood pressure decreases in anesthetized normotensive rats, thus manifesting itself as a hypotensive agent.

The process for the preparation of the compounds of the formula (X) according to the invention consists of reactions of methoxyphenoxyacetic acid derivatives of the formula (II)

R

CH ₃ OOCH ₂ COR ² (II),

Wherein R is the same as in Formula I and R is chlorine or methoxy, with primary amino compounds of Formula III

H ₂ NR ² (III), wherein R ² is the same as in Formula I. These reactions can be performed under various conditions.

When 4-methoxyphenoxyaoethyl chloride (II, R = HR = Cl) is used (Fridman SG, Z. Obsc. Chim. 24, 642, 1954) as the starting material, its reaction with the compounds of formula III used in 100% excess, in boiling chloroform. The compounds of the general formula III used are generally known and are the following: 2-phenylethylamine (commercially available), isopropy lhydrazine (Kost AN, Sagitullin RS, Z. Ob. Chim. 33, 867, 1963), 1-aminopiperidine (Zimmer H) et al., J. Am. Chem. Soc., 77, 790 (1955) and 4-aminomorpholine (Zimmer H. et al., supra). If 3,4,5-trimethoxyphenoxyacetic acid methyl ester (Protiva M. et al., Collect. Czech. Chem. Commun. 42, 3628, 1977) is used, the reaction with the compounds of the formula III must be carried out at elevated temperature: at least boiling ethanol) more preferably in the above boiling solvents (e.g. boiling mixture of toluene and butanol), or without environment by heating the components to 100-150 ° C. The compounds of the invention are generally crystalline, so that they can be purified by crystallization. Hydrazides are monobasic compounds and provide crystalline salts, primarily hydrochlorides. All substances described in the invention are novel. Their identity was ensured both by analyzes and by usual spectral methods.

Further details of the preparation of the compounds according to the invention are given in the examples, which are intended to illustrate the possibilities of the invention, but are not intended to be exhaustive.

Example l

N- (2-phenylethyl) -4-methoxyphenoxyacetamide

To a stirred solution of 4.84 g of 2-phenylethylamine in 20 ml of chloroform was added dropwise a solution of 4.2 g of 4-methoxyphenoxyacetyl chloride in 10 ml of chloroform. The reaction is exothermic and the mixture is brought to reflux without external heating. The mixture was stirred for 4 h, allowed to stand at room temperature overnight, the precipitated 2-phenylethylamine hydrochloride (3.1 g) was filtered off with suction the next day and washed with chloroform. The filtrate was washed with water, dried and evaporated. The residue crystallizes on standing and is the desired product in a yield of 5.7 g (100%) which, after crystallization from toluene / petroleum ether, melts at 80-81.5 ° C.

Example 2

N- (2-phenylethyl) -3,4,5-trimethoxyphenoxyacetamide

A mixture of 5.12 g of 3,4,5-trimethoxyphenoxyacetic acid methyl ester, 3.02 g of 2-phenylethylamine and 15 ml of ethanol is refluxed for 10 h and evaporated under reduced pressure. The solid residue (6.9 g, 100%) was crystallized from aqueous methanol. The pure product melts for the first time at 90-92 ° C, solidifies with further heating and finally melts at 98 ° C.

Example 3

1- (3,4,5-trimethoxyphenoxyacetyl) -2- (2-propyl) hydrazine

A mixture of 7.7 g of 3,4,5-trimethoxyphenoxyacetic acid methyl ester, 4.5 g of isopropylhydrazine and 0.05 g of sodium methoxide is stirred and refluxed at 100 to 120 ° C for 12 h.

After partial cooling, the melt is dissolved in 250 ml of benzene, the solution is washed with water and the basic product is extracted into 75 ml of 2.5M-HCl. The separated aqueous solution was basified with 20 ml conc. aqueous ammonia and the product was extracted with benzene. Workup of the extract yielded 7.9 g (88%) of the desired material which crystallized from a mixture of cyclohexane and benzene and melted pure at 80-81.5 ° C. Treatment with an ethereal solution of hydrogen chloride in 2-propanol gives the hydrochloride melting at 180.5-182.5 ° C.

He attaches

1- (3,4,5-trimethoxyphenoxyacetamido) piperidine

A mixture of 8.3 g of 3,4,5-trimethoxyphenoxyacetic acid methyl ester, 3.5 g of 1-aminopiperidine, ml of toluene, 25 ml of butanol and 0.05 g of sodium methoxide is stirred and refluxed for 4 hours. A portion of the solvents (15 mL) was distilled off and the residue was left overnight. The precipitated crystalline product is filtered and recrystallized from 18 ml of methanol. The title compound was obtained in a yield of 3.0 g (29%); after further crystallization from methanol, it is completely pure and melts at 156.5-158 ° C.

Example 5

4- (3,4,5-trimethoxyphenoxyacetamido) morpholine

A mixture of 7.7 g of 3,4,5-trimethoxyphenoxyacetic acid methyl ester, 4.6 g of 4-aminomorpholine and 0.05 g of sodium methoxide is stirred and refluxed at 120 to 125 ° C for 3 h.

After cooling, the melt is dissolved in 200 ml of chloroform, the solution is washed with water, dried and evaporated. 5.4 g (55%) of crystalline product are obtained, which is recrystallized from benzene, m.p. 144.5-146.5 ° C.

Claims (3)

SUBJECT OF THE INVENTION A process for the preparation of novel amides and hydrazides of methoxyphenoxyacetic acids of general formula I R CH ₃ or OCH ₂ CONHR wherein R is hydrogen or methoxy and R ¹ is 2-phenylethyl, isopropylamino), piperidino or morpholino, characterized in that the methoxyfenoxyoctových derivatives of the formula II R ch ₃ o -och ₂ cor ² (II), "2 in which R denotes the same as in formula I and R is chlorine or methoxy, reacts with the primary amino compounds of formula III HJN-R ¹ in which R ⁴ has the same meaning as in formula I. 2. A process according to claim 1, wherein 4-methoxyphenoxyacetyl chloride is used as the starting material of formula II, the compound of formula III is reacted with it in 100% excess, and the reaction is carried out in boiling chloroform. 3. Process according to claim 1, characterized in that as starting materials of formula II used is 2 methyl ester of formula II wherein R = OCH _3, the compound of formula II is used in excess from 5 to 20%, and reaction of the components may be performed either in boiling solvents preferably ethanol, toluene or butanol, or without medium at 100 to 150 ° C in the presence of trace amounts of sodium methoxide.