CS226945B1 - Method of preparing hydroxyeburnate - Google Patents

Description

The invention relates to a process for the preparation of hydroxyeburnanes of the general formula I,

in which R ¹ represents a hydrogen atom with the configuration or β, R ² OH group when R ³ represents a methoxycarbonyl or ethoxycarbonyl, or ^R2 is methoxycarbonyl or ethoxycarbonyl, where R ³ represents a hydroxyl group, both their raceimaids and optically active forms.

Compounds of formula I which exhibit significant cerebrovascular activity are generally known. One of these compounds, vincamine (I, R ¹ = Η, R ² = OH, R ³ - COOCH ³ J) is an important drug in this indication area, and these compounds can also serve as valuable raw materials for the production of other active drugs.

According to the procedure in MS. No. 189,620 produces a mixture of vincamine (I, R ¹ = Η, R ² = OH, R ³ = COOCH ₃ ) and its stereoisomer of 16-epivincamine (I, R ¹ = Η, R ² = (COOCH ³ and R ³ = OH) by reacting to deoxyvincamine of formula II,

where R @ ¹ represents a hydrogen atom in the aa configuration and R @ ² 'represents a methoxy group having the -a configuration, acts in the aprotic solvent with a strong organic base and then with molecular oxygen. Yields not shown. In reproducing this process, it was found that the yields of the desired products were very low. A further disadvantage of said process is the long reaction time of the oxidation stage. It is an object of the present invention to overcome these disadvantages.

The process according to the invention is characterized in that the racemates or optically active forms of the esters of the 16-carboxyeburnanes of the formula II in which R @ ¹ represents a hydrogen atom having the α or β configuration and R @ ² 'are a methoxy or ethoxycarbonyl group having the. , in strong aprotic solvent, such as anhydrous tetrahydrofuran, hexamethylphosphoric triamide or mixtures thereof, with a strong organic base, e.g. lithium diisopropylamide at temperatures from -78 to +100 ° C, preferably at 0 ° C, followed by oxidation with molybdenum peroxide as the complex of formula III,

MoO5.Py.HMPA (III) wherein Py is pyridine and HMPA is hexamethylphosphoric triamide.

The following examples illustrate but do not limit the generality of the process of the invention.

Example 1

To a solution of lithium diisopropylamide prepared from diisopropylamine (0.3 mL, 2.1 mmol) and 15% butyllithium solution (1.4 mL,

2.25 mmol) in tetrahydrofuran (3.0 mL) at 0 ° C was added dropwise a solution of 0.2 g (0.6 mmol) of (+) - methyl-deoxyvincaminate (II, R ¹ = Η, R 2 '- aCOOCH 3). ) in tetrahydrofuran (8.0 mL) and the reaction mixture was stirred at 0 ° C for 0.5 h. After a single addition of MoO5.Py.HMPA complex reagent (0.28 g), stirring was continued for an additional 0.25 h at 0 ° C. ° C and 0.25 h at 20 ° C. The solution was recooled to 0 ° C, stirred for an additional 2 hours at 20 ° C after the addition of an additional 0.12 grams of oxidizing agent. The reaction mixture was quenched with 5 milliliter of water, the phases were separated and the aqueous layer was extracted with chloroform. The combined organic phases were evaporated to dryness and the residue was chromatographed on a silica gel column. Treatment of the methanol-chloroiform relevant fractions yielded 8.1 mg (+) - vincamine (I, R ¹ - = H, R ² = OH, R ³ = COOCH 3) melting, m.p. 232-234 ° C, 84.5 mg (-) - 16-epivincamine (I, R ¹ = Η, R ² = COOCH ₃ , R ³ = = OH), m.p. 188-190 ° C.

Example 2

To a solution of lithium diisopropylamide prepared from diisopropylamine (0.5 mL in tetrahydrofuran (5 mL) and a 15% solution of butyllithium in hexane (2.5 mL) at 0 ° C was added dropwise a solution. 0.35 g (+] -21/3 16/3-ethoxykarbonyleburnanu (II, R ¹ - / 3 H, R ² = / ICOOCaHs) in 5 ml of tetrahydrofuran and the mixture was stirred at 0 ° C for 0.5 hr. was then added as described in Example 1 of 0,675 g MoO complex oxidizing _fifth Py. HMPA. the reaction mixture was stirred at room temperature for 2.5 hours, then quenched in 7 ml water and treated as in Example 1 gave (+) - ethyl-16-epi, 21-epivincamine (I, R ¹ = j3H ^R2 = COOC2H5, R 3 - one), m.p. 146-148 ° C and (+) ethyl-21-epivincamine (I, R = ^1/3 H, R ² = OH, R ³ = COOC (2H) m.p. 181-183 ° C.

Claims (1)

Subject Method for producing hydroxyeburnanů formula I, the invention they racemates and optically active forms, characterized in that the racemates or optically active forms of the esters 16 karboxyeburnanů formula II in which R ¹ represents a hydrogen atom with the configuration or β, R ² a hydroxyl group when R ³ represents a methoxycarbonyl or ethoxycarbonyl group, or R ² represents a methoxycarbonyl or ethoxycarbonyl group when R ³ represents a hydroxyl group, as in which R ¹ represents a hydrogen atom of the «or β configuration and R ² the methoxy or ethoxycarbonyl group having the α or β configuration, acts in an aprotic solvent such as anhydrous tetrahydrofuran, hexamethylphosphoric triamide or mixtures thereof, with a strong organic base, e.g. lithium diisopropylamide, at temperatures from -78 to 100 ° C, preferably at 0 ° C, followed by oxidation with molybdenum peroxide in the form of cpl exu of formula III, MoO _s . Py. HMPA wherein Py denotes pyridine and HMPA selines hexamethylphosphoric. (III) tri-