CS252844B2 - Method of 3-phenyl-2-propenamine's new derivative production - Google Patents

Abstract

Method of production of a new 3-phenyl- Of 2-propenamine of formula I C = CH - CH, I 2 CHOH-C.Hc- CH, (AND) isomer E and salts acceptable from a pharmaceutical standpoint, characterized by by the fact that it is organomagnesium a derivative of formula III MgXo (III) where XQ represents a halogen atom, na of Formula IV C.Hc - CH - C - C - CH, - N 6 5 »2 OH compound CH, (IV) CH ~ O N whereupon the resulting product is isolated optionally converting it to a salt acceptable from a pharmaceutical standpoint. Compound Formula I can be used as medicine antidepressant.

Description

(54) A process for the preparation of a novel derivative of .beta.-furan-1-Z-propenamine

A process for the preparation of a novel 3-phenyl-2-propenamine derivative of the formula I

C = CH-CH,

I ²

CHOH-C.Hc6 5

CH,

(I) in the form of an E isomer and pharmaceutically acceptable salts, characterized in that it is treated with an organomagnesium derivative of the general formula III

MgX _o (III) where

X _Q represents a halogen atom, to the formula IV

CH _c - CH - C - C - CH, - N 6 5 2

OH compound

CH, (IV)

Whereupon the resulting product is isolated and optionally converted into a pharmaceutically acceptable salt. The compound of formula I may be used in medicine as an antidepressant.

The invention relates to a process for the preparation of a novel 3-phenyl-2-propenamine derivative of the formula I ch ₃ (I) ^CH 3

CHOH-C 8 H 8 and isomer of Form E and pharmaceutically acceptable salts thereof.

In carrying out the process of the invention, a compound of formula I can be obtained by treatment with an organomagnesium derivative of formula III

(III) where

X _Q represents a halogen atom, preferably a bromine atom, to a compound of formula IV CH,

C, H _c - CH - CS c - CH, - N 6 5 I ² \

ÍH

CH, (IV).

The procedure is in the art for reacting an organomagnesium derivative to an acetylene derivative without affecting the rest of the molecule.

The product of formula (IV) can be obtained by treatment of benzaldehyde with dimethylpropargylamine of formula (V) ^CH3 (V).

CH,

The reaction is usually carried out in an inert organic solvent, for example 1,2-dimethoxyethane at a temperature in the range of -40 to 0 ° C after introduction of the metal into dimethylpropargylamine by any means, for example by treatment with an organometallic base such as n-butyllithium in hexane at -70. Deň: 32 ° C.

Dimethylpropargylamine can be obtained by treating dimethylamine on propargyl bromide according to M. Gaudemar, Ann, Chim. (France) 13,161,1956.

The novel compounds of formula (I) may be purified in conventional manner, for example by crystallization, chromatography or sequential extraction in an acidic and basic medium.

The novel compounds of formula (I) may optionally be converted into acid addition salts in an organic solvent, for example an alcohol, a ketone, an ester or a chlorinated solvent. The resulting salt precipitates upon optional concentration of the solution and is then separated by filtration or decantation.

The novel compounds of formula (I) and their salts have interesting pharmacological properties which permit their use as antidepressants.

These compounds are effective, for example, as antagonist compounds in the case of depression induced by tetrabenazine in mice at doses of 1 to 100 mg / kg orally.

The dose of DL 40 for the compounds produced by the process of the invention is generally in the range of 50 to 900 mg / kg when administered orally.

From Belgian patent specification no. No. 781,105 are known 2-propenamine derivatives with antidepressant properties. However, none of the resulting products contains a -CHOH- group in the molecule, and no other known publication indicates that this group has ever been incorporated into the compounds.

The compounds of the invention may be used in medicine as such or in the form of a pharmaceutically acceptable salt thereof, i.e., non-toxic, at the dosages administered.

Examples of pharmaceutically useful salts include salts with inorganic acids such as hydrochlorides, sulfates, nitrates, phosphates, or salts with organic acids such as acetates, propionates, succinates, benzoates, fumarates, maleates, methanesulfonates, isothioates, theophyllinacetates , salicylates, phenolphthaleinates, methylene-bis-naphthoates or substitution derivatives of the above compounds.

The following examples illustrate the practice of the present invention. In some examples, the resulting products were purified by high speed short column chromatography at about 50 kPa pressure using silica with a particle size of 40-63 µm as described by WC Still, M. Kahn and A. Mitra, J. Org. . Chem. 43, 2923 (1978).

Example

To a suspension of 3.85 g of magnesium grafts in 100 mL of ethyl ether was added dropwise over 1 hour a solution of 24.8 g of bromobenzene in 120 mL of ethyl ether. 10 g of 4-diamethylamino-1-phenyl-2-butin-1-ol in 30 ml of ethyl ether are added to the obtained black solution over 15 minutes.

The reaction mixture was heated to reflux for 3 hours 30 minutes and then poured into a mixture of 400 g of ice and 200 ml of saturated aqueous ammonium chloride solution.

The organic phase is separated by decantation and the aqueous phase is extracted twice with 200 ml of methylene chloride. The organic phases are combined, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure of 2.7 kPa at 40 ° C. The residue was purified by flash chromatography, eluting with a 60:40 mixture of methanol and ethyl acetate. Fractions 18 to 39 are combined and evaporated to dryness under reduced pressure of 2.7 kPa at 40 ° C. 3.9 g of 4, dimethylamino-1,2-diphenyl-2-butin-1-ol (E) are obtained in the form of a white crystalline solid, m.p. 113 DEG C., after recrystallization of the residue from isopropyl ether.

4-Dimethylamino-1-phenyl-2-butin-1-ol can be obtained as follows:

To a solution of 33.2 g of Ν, Ν-dimethylpropargylamine in 4 ml of 1,2-dimethoxyethane under a nitrogen atmosphere at about -70 ° C was added 280 ml of a 1.55 roztoku solution of n-butyllithium in hexane. A solution of 42.4 g of benzaldehyde in 100 ml of 1,2-dimethoxyethane is added to the suspension obtained at about -30 ° C. The reaction mixture is stirred for 30 minutes at about 0 ° C and then 20 ml of distilled water are added. The resulting suspension was filtered. The solution was dried (MgSO4), filtered and evaporated. to dryness under reduced pressure of 2.7 kPa at 40 ° C. 72.3 g of 4-dimethylamino-1-phenyl-2-butin-1-ol are obtained in the form of a yellow oil, Rf 0.56, by thin-layer chromatography on alumina using ethyl acetate as eluent.

Claims (1)

OBJECT OF THE INVENTION A process for the preparation of a novel 3-phenyl-2-propenamine derivative of the formula I in the form of the E isomer and pharmaceutically acceptable salts thereof, characterized in that it is treated with an organomagnesium derivative of the general formula XIX MgX _o (III) where Χθ is halogen, to a compound of Formula IV 0Η ₃ C, H _r - CH - C »C - CH, - N ^{6 6} I ² \ I ^X CH OH ⁰ then the product is isolated and optionally converted into the E isomer and / or salt thereof into a pharmaceutically acceptable.