HU182818B - Process for preparing new oxyamino-eburnan deriavtives - Google Patents

Abstract

The present invention relates to a 14-epimer mixture of novel oxyaminobumane derivatives of the formula V wherein R1 and R2 are C1-C4 alkyl, and R3 is halogen-substituted phenyl: C1- (C1-C4) alkyl - or an acid addition salt thereof, by the addition of an oxyamino-E-homoburnan derivative of formula IV wherein R2 and R3 are as defined above, by addition of an alkali metal to an alcohol of formula R1-OH wherein R1 is as defined above. and, if desired, converting the resulting oxyaminoburnan 14-epimer mixture of formula V to an acid addition salt. The oxyaminobumane compounds of formula V are novel. They are important because they may be the starting material for the pharmacologically significant apovinkamic acid ester derivatives having vasodilatory activity. IV 0-R3 V -1-

Description

The present invention relates to a 14-epimeric mixture of novel oxyamino-ebumane compounds of formula V wherein R 1 and R 2 are C 1 -C 4 alkyl, R 3 is halogen-substituted phenyl (C 1 -C 4) alkyl, and acid addition salts thereof, by adding an oxyamino-E-homoeburnan derivative of formula IV, wherein R ₂ and R ₃ are as defined above, to an alkali metal of formula R 1 -OH, wherein R 1 and reacting, if desired, the resulting oxyamino-ebuman 14-epimer mixture of formula V, wherein R ₁ and R ₂ and R ₃ are as defined above, into the acid addition salt.

The compounds of formula V are novel, and of particular importance is the fact that they are used in one step to obtain a pharmaceutically significant, vasodilating ester derivative of apovincaminic acid.

The novel compounds of formula IV used as starting materials in the process of the present invention are prepared by reacting the corresponding racemic or optically active dioxo-E-homo-ebuman with a hydroxylamine derivative or a salt thereof. The process is described in more detail in our co-pending patent application.

Process of this invention the compound of formula IV compound and the R-OH - wherein R is as defined above - is carried out in the presence of a reaction of an alkaline agent, the compound of new V obtained - wherein R, R ₂ and R ₃ have the as defined above, can be well isolated and identified from the reaction mixture. In this case, it is expedient to prepare the metal and the excess alcohol R1-OH to form an alcoholic metal alcoholate solution and to dissolve the compound IV.

The reaction is conveniently carried out under reflux for 1/2 to 3 hours.

During the process, the novel oxyamino-ebuman compounds of formula V are obtained in the form of a 14-epimer mixture. If desired, this oxyamino-eburnan 14-epimer mixture may be converted into an acid addition salt.

The novel oxyamino ebumane compounds of Formula V are prepared in a manner that is readily identifiable by the process of the present invention, which is clearly evidenced by the position of the bands of the characteristic groups as measured by infrared spectroscopy and mass spectral values.

The invention is illustrated in more detail by the following non-limiting examples.

/. Example (+) -3 (S), 17 (S) -14-oxo-15- (p-chlorobenzyloxyamino) -E-homo-eburnan

Of a solution of 0.33 g (1.02 mmol) of (+) - 3 (S), 17 (S) -14,15-dioxo-E-homoeburnane (see RI-690) in 1.6 ml of absolute pyridine. , 33 g (1.7 mmol)

Hydrochloric acid salt of O- (p-chlorobenzyl) hydroxylamine was added and the reaction mixture was heated on a water bath for 2 hours. The solvent was removed in vacuo and the residue was washed with water and dried.

0.40 g of the title compound is obtained, which can be carried on to the next reaction without purification.

Yield: 84.5%.

If the Ζ, geomet-geometric isomers are to be separated, the above 0.40 g is recrystallized from 3 ml of methanol.

Run over 0.22 g of a single KG-G sheet in a 14: 3 mixture of benzene / methanol to give a higher Rf isomer.

136-137 ° C (from methanol).

Infrared (potassium bromide): 1695 (lactam CO), 1590 cm ^-1 (aromatic).

Mass Spectrum (m / e%): 461 (M + 40).

Mp = + 151 ° (c = 1, dichloromethane).

The methanolic mother liquor was purified by preparative layer chromatography (KG-54 PO _{2 +} A66, benzene-methanol 14: 3 mixture) gave an additional 60 mg of higher Rf value of isomer (total yield: 0.28 g) and 35 mg of lower Rf isomer we produce.

Melting point: 177 DEG C. (from ether).

IR (potassium bromide): 1685 (Yakfam CO), 1585 cm @ ^-1 (aromatic).

MS: (m / e%): 461 (M + 40).

Example 2

3 (S), 14 (S), 17 (S) - 14-ethoxycarbonyl-14- (p-chlorobenzyloxyamino) -eburnane and 3 (S), 14 (R), 17 (S) -14-ethoxycarbonyl-. 14- (p-Chlorobenzyloxyamino) -eburnane

0.20 g (0.43 mmol) of (+) - 3 (S), 17 (S) - 14 - oxo-15 - (p-chlorobenzyloxyamino) -? mg of a solution of sodium metal in ml and absolute ethanol (ml) was added and the reaction mixture was refluxed in a water bath (calcium chloride tube) for 1.5 hours. The progress of the reaction can be monitored by thin layer chromatography (KG-G, benzene / methanol 14: 2, starting material Rf greater than final product Rf). After the reaction, a few drops of glacial acetic acid were added to adjust the pH to 6 and the solvent was removed by distillation in vacuo. Water was added to the evaporation residue, the solution was basified to pH 8 with aqueous sodium bicarbonate solution and extracted with dichloromethane (3 x 5 mL). The dichloromethane solution was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by evaporation.

There was thus obtained 0.20 g of the title compound as an oil.

0.20 g is dissolved in 1 ml of ethanol and the solution is adjusted to pH 5 with hydrochloric ethanol, then 1.0 ml of ether is added and the hydrochloride salt of the precipitated 14-epimer mixture is filtered, washed with ether and dried.

0.17 g of the title epimer mixture was prepared in the form of hydrochloride.

Yield: 76%.

182,818

The mixture salt melts at 135 ° C.

Infrared (potassium bromide): 3200 (NH),

1718 cm <^-1> (ester CO).

MS: (m / e%): (M 507, 20).

Claims (2)

Patent claims A process for the preparation of a 14-epimer mixture of a novel oxyamino-eburnan compound of formula V wherein R 1 and R 1 are C 1 -C 4 alkyl, R 3 is halo-substituted phenyl (C 1 -C 4) alkyl, or acid addition salts thereof. characterized in that an oxyamino-E-homo-15-butane derivative of Formula IV wherein R2 and R3 are as defined above for V is added with an alcohol of the formula R1-OH wherein R1 is reacting a compound of formula V as defined above, and optionally converting the resulting oxyamino-ebuman 14-epimer mixture of formula V, wherein R1, R2 and R3 are as defined above, into the acid addition salt. 2. A process according to claim 1 wherein the alkali metal is first dissolved in an alcohol of the formula R 1 -OH, wherein R 1 is The reaction is as defined in claim 1 and the reaction is carried out in the presence of an alkali metal alcohol of formula R1-OMe, wherein R1 is as defined in claim 1 and Me is an alkali metal atom.