DK143562B - PROCEDURE FOR THE PREPARATION OF (-) - VINCAMIN - Google Patents

Description

143562

The present invention relates to a particular process for the preparation of (-) - vincamine of the formula;

CoO »f | (V) H0 - \ / \ /

/ I

/! h3cooc '\

V

The (-) - vincamine produced is an intermediate in the synthesis of both natural vincamine and epi-16 vincamine as well as apo-vinca min.

It is known that vincamine and apple vincamine are alkaloids which can be isolated from Vinca minor. When dehydrated in an acidic environment, these two products give the same derivative, apo-vincamine.

Vincamine and its derivatives present interesting pharmacological properties of therapeutic use. However, their use is limited due to the fact that Vinca minor contains only a little vincamine and very little epi-16-vincamine, and that these two alkaloids as well as apo-vincamine and other derived products are expensive substances.

Several methods are known for the synthesis of vincamine and its derivatives, but these known methods give only poor yield and lead to racemic products.

The object of the present invention is to provide a simple and selective process for producing (-) - vincamine in high yield.

This object is achieved according to the invention by a method characterized in that (-) - tabersonin of the formula: C0

OcOn i T! C00CH3 in a first step is catalytically hydrogenated to give almost quantitative yield of (-) - vincadifformin of the formula: rVir- 'Vr in H C00CH3' amount of a peroxide to convert in this second step to (-) - vincadifformin N-oxide of the formula: 0

HriV'-

H

cooch3; and that the (-) - vincadifformin-N-oxide thus obtained is again treated in a third step with an equimolar amount of a peroxide to give (-) - 1β-dehydro-16-carbomethoxy-16-hydroxy-aspidospermidine-N - oxide of the formula: 0 noW-uv) C00CH3 or (b) treated with two moles of peroxide per mole (-) - vincadifformin for a longer time to directly form (-) - 1,2-dehydro-16-carbomethoxy - 16-hydroxy-aspido-spermidine-N-oxide of formula IV, and the compound of formula IV is treated with an equimolar amount of triphenylphosphine or with another reducing agent for the N-oxide group in an acidic environment to rearrange the product into a mixture of (-) - vincamine, 16-epi-vincamine and apo-vincamine, then ( -) - vincamine is extracted.

Danish Patent Application No. 1531/71 discloses a process for the preparation of (-) - vincamine from cis-1,2,3,4,6,7, 12,12b-octahydro-1β-ethyl-1of-carbomethoxyβthyl -12bβ-indolo- (2,3-a) quinazoline. This compound is converted to a lactam compound, 14-oxo-, (20) -E-homo-eburnan, which over the corresponding hydroxy-imino compound, 14-oxo-15-hydroxyimino-35, (20) -E-homo -eburnan and dioxo compound, 14,15-Ρΐοχο-3β, 16β (20) “Ε- | · ιοτηο-βηυΓη3η is converted to (-) - vincamine.

In the practical implementation of the process according to the invention, the tabersonin used as a starting material may be obtained from Voacanga grains, where this alkaloid is available in relatively large quantities. The preparation of tabersonin is conveniently carried out by the method disclosed in French Patent Application No. 69 09 002.

As mentioned, the final step rearrangement of the process according to the invention results in a mixture of (-) - vincamine (V), epi-16 - vincamine (VI) and apo-vincamine (VII) having the following formulas: ccci, ooa cc® .

H0 — H3C00C H-COOC

, v /! 3 I

/; / j I

HjCOOC7 H0 (V) (VI) (VII)

By means of chromatography, the mixture thus obtained can be separated into two fractions. The most polar fraction consists of a major amount of vincamine and a smaller amount of epi-vincamine which can be separated by crystallization. The least polar fraction gives crystallisaton apo-vincamine.

143562 4

The fractionation of compounds V, VI and VII can be carried out by several successive crystallizations without using chromatography.

Specifically, the various steps of the process of the present invention are conveniently carried out as follows: In the first step, (-) - tabersonin, which is dissolved in an alcohol at ordinary pressure, is hydrogenated in the presence of a catalyst such as PtOg or Pd / C for uptake of theoretical volume. The catalyst is separated from the solution by filtration on diatomaceous earth. The solution is evaporated in vacuo. The residue is crystallized in a methanol-ether mixture. Melting point 96 ° C (a) D = -600 ° (ethanol).

In the second step, (-) - vincadifformin is treated for 1-5 hours with an equimolar amount of a peracid at ordinary temperature in a nitrogen atmosphere without the light's access in a water-immiscible and aromatic solvent such as benzene or toluene, of the ether oxide type or of a type consisting of a chlorinated aliphatic hydrocarbon derived from methane or ethane such as methylene chloride, carbon tetrachloride, chloroform or trichloroethylene or tetrachloroethane.

The reaction solution is washed with an aqueous alkaline solution to remove the bulk of the peroxidizing agent and its conversion products, then distilled to give a residue consisting of (-) - vincadifformin N-oxide (III) and present in a yield of about 90% . As such, this can be converted to (IV) or it can first be purified by crystallization in a mixture of volatile solvents.

Melting point: 160 ° C (decomposition) (a) D = -213 (C = 1 methanol) U.V. (methanol max. at λ log ε: 228 (3.99), 297 (3.99) and 331 (4.11) nm

Mass spectrum molecular peak N + at m / e 354

Analysis C21H26 ° 3N2 calculated% C 71.17 H 7.39 found% C 70.9 H 7.3 In the third step, (-) - vincadifformin N-oxide (III) is treated with an equimolar amount of a peracid as in the previous step but for 1-5 days to obtain in a yield about 80% of (-) - 1,2-dihydro-16-carbomethoxy-16-hydroxy-aspidospermidine N-oxide (IV) which can be purified by crystallization in a volatile solvent or as such is used in the fourth step of the process.

Melting point: 178-180 ° C (decomposition) (ot) p = 107 ° (C = 1 methanol) U.V. (methanol) max. at λ log ε: 223 (4.29), 270 (3.73) nm »1 I.R. carbonyl ester non-conjugated 1738 cm Mass spectrum molecular peak M + at m / e 370 Analysis C21H26 ° 4N2 Calcd% C 68.09 H 7.07 Found% C 67.9 H 7.0

The peracids used in the second and third steps may be the same or different. They can be the following: Peracetic acid, perbenzoic acid, metachloroperbenzoic acid, paranitroperbenzoic acid, trifluoro-peracetic acid, permyric acid, perphthalic acid.

As mentioned, it is not necessary to isolate the intermediate (III), but (-) - vincadifformin (II) can be treated with a double equimolar amount of peracid under the conditions defined above for 1-5 days. A yield of about 85% is thus obtained.

A preferred embodiment of the process according to the invention is characterized in that the compound of formula IV and an equimolar amount of triphenylphosphine are dissolved in a low molecular weight liquid organic acid and preferably in acetic acid, so that the solution is cooled, after two hours, in an atmosphere of nitrogen. large amount of water and washed with twice the amount of benzene or ether to remove the resulting triphenylphosphine oxide that the volatile organic phase is removed by decantation, then the acidic aqueous phase is then made alkaline to a pH of 10 and extracted with an organic solvent, the organic phase is decanted off, washed with pure water and dried over a water absorbent, and finally the solvent is removed by distillation.

This embodiment offers the advantage that the reagents used are triphenylphosphine and acetic acid are easy to use and are readily available compounds, and that a good yield is obtained, namely approx. 85%.

143562 6

To isolate (-) - vincamine (V), epi-16-vincamine (VI) and apo-vincamine, the crude residue from the previous reaction is dissolved in 10 parts of benzene and chromatographed on a column of 30 parts of alumina. The elution is carried out successively with benzene, a mixture of benzene and ether (80-20) and pure ether. Upon crystallization in acetone, each of these fractions gives apo-vincamine (VII), vincamine (V) and epi-16-vincamine (VI), respectively, in about amounts of about 25%, 50% and 25%.

The treatment of the compound of formula IV with triphenylphosphine is preferably carried out at room temperature over about 30 minutes. 12 hours in aqueous acetic acid environment. The untreated product thus obtained is obtained in a yield of about 85% and contains very little apo-vincamine (VII), and vincamine (V) and epi-16-vincamine (VI) in a ratio of 3: 1. From this mixture, the vincamine can be isolated by two crystallizations in acetone, methanol, ethanol or propanol.

The following examples illustrate the characteristic features of the method of the present invention.

EXAMPLE 1 a) Preparation of (-) - vincadifformin (II) from (I)

A constantly stirred slurry of 200 g of Adams platinum oxide in 10 liters of methanol is saturated with hydrogen for one hour at room temperature and pressure, then a solution of 1 kg of tabersonin in 10 liters of methanol is rapidly added and stirring is continued. The theoretical amount of hydrogen is absorbed within 6 hours. The catalyst is then removed by filtration on diatomaceous earth and the filtrate distilled to dryness to give 985 g of hydrogenated derivative (II) in the form of a transparent lacquer which, by recrystallization in a methanol-ether mixture, gives (-) - vincadifformin. Melting point 96 ° C (o 0 = -600 ° (ethanol)).

b) Preparation of (-) - vincadifformin N-oxide (III) from (-) - vincadifformin (II)

A solution of 1.3 kg of (-) - vincadifformin and 800 g of paranitroperbenzoic acid in 200 liters of dry benzene is recommended in a nitrogen atmosphere and in the absence of light. After 4 hours under these conditions, a thin layer of silica gel (eluent: benzene 50, methanol 39, ether 10 and ammonia 1) was checked by plate chromatography for a sample showing the complete disappearance of the original blue stain provided by the (-) - vincadff formulated with the ammoniacal cerium sulfate reactant and its replacement with another blue stain with clearly less Rf. The benzene solution is then washed with a sodium hydrogen carbonate solution and with water. After drying the benzene solution and distilling off the solvent, a thick oil weighing 1,380 kg (90% yield) is obtained which, by recrystallization in a methylene chloride-ether mixture, gives (-) - vincadifformin-N-oxide (III). Melting point 160 ° C.

c) Preparation of (-) 1,2-dehydro-16-carboroethoxy-16 hydroxy-aspido-spermidine N-oxide (IV) from (III)

A solution of 1,410 kg (-) - vincadifformin N-oxide (111) and 800 g of paranitroperbenzoic acid in 200 liters of dry benzene is left in a nitrogen atmosphere and in the absence of light. After 4 days under these conditions, a thin-layer chromatography check was performed for a sample showing complete disappearance of the original blue spot showing (-) - vincadifformin N-oxide with the ammonia-based reagent cerium sulphate and its replacement with a product which is not developed with said reagent but which gives a brown stain with the Dragendorff reagent.

The reaction solution is then treated as in the previous experiment. Finally, a thick oil weighing 1,320 kg (yield 89%) is obtained, which knows about crystallization in a methylene chloride-ether mixture gives the product (IV) in crystallized form. Melting point 178-180 ° C during decomposition.

d) Preparation of (-) - vincamine (V), epi-16-vincamine (VI) and apo-vinamine (VIII) from (IV) by rearrangement

A solution of 1,110 kg of (VI) and 780 g of triphenylphosphine in 100 liters of pure acetic acid is heated under reflux for 2 hours. The reaction solution is diluted with an equal volume of ice water and washed with 50 liters of benzene which removes 120 g of triphenylphosphine oxide. The solution is then made alkaline by means of sodium hydrogen carbonate and extracted twice with 50 liters of methylene chloride. The methylene chloride solutions, after washing with water and drying by distillation, give an oily residue weighing 950 g (yield 86%).

An analysis by thin layer chromatography shows with U3562 8

The Dragendorff reagent is present in this oily residue of three constituents having the same Rf value as apo-vincamine, vincamine and epi-16-vicamine in order of decreasing Rf value. This oily residue is chromatographed dissolved in 10 liters of benzene on a column of 30 kg alumina. By successive elutions with benzene, benzene-20% ether mixtures, and pure ether, three fractions are obtained which, upon recrystallization in acetone, yield three pure products which are identified by their physical constants (F, (0 O, UV, IR, mass spectrum) with reference samples such as: apo-vincamine (VII) (120 g), vincamine (V) (330 g) and epi-16-vincamine (VI) (150 g). The same reaction between (IV) and the triphenylphosphine conducted in acetic acid in the same conditions but at room temperature for 12 hours yielded 85% of a crude mixture containing only traces of apo-vincamine and consisting largely of vincamine (V) (3 parts) and epi-16-vincamine ( VI) (1 part).

EXAMPLE 2

Preparation of (-) - 1,2-dehydro-16-carbomethoxy-16-hydroxy-aspido-spermidine N-oxide (IV) ex from (II)

A solution of 1,360 kg (-) - vincadifformin (II) and 1,600 kg of paranitroperbenzoic acid in 200 liters of dry benzene is left for 5 days in a nitrogen atmosphere and in the absence of light. In this step, a control by thin-layer chromatography shows the disappearance of the starting material (II) and the intermediate (III) and their replacement with (IV). The reaction solution, treated as in the previous examples, leads to isolation to 1,250 kg of derivative (IV). Yield 84%.

The same reaction carried out in dry methylene chloride instead of benzene leads to the same derivative (IV) with a yield of 80%.

Claims (2)

143562 A process for the preparation of (-) - vincamine of the formula: OgCCl (V) h ° - / I / I * H_COOC / L 3 characterized by, a (-) - tea person of the formula: Ol- i a_V> r ( (i) In a first step, H COOCH3 is catalytically hydrogenated to give almost quantitative yield of (-) - vincadifformin of the formula: - (II) "Ί H COOCH3! a) is either treated with an equimolar amount of a peroxide to convert, in a second step, this compound to (-) - vincadifformin-N-oxide of the formula: (III) obtained (-) - vincadifformin N-oxide in a third step is again treated with an equimolar amount of a peroxide to give (-) - 1,2-dehydro-16-carbomethoxy-16-hydroxy-aspidospermidine N-oxide with the formula: 0 (IV) ΓΓ; cooch3 or (b) is treated with two moles of peroxide per ml. molar (-) - vincadifformin for an extended period to directly form (-) - 1,2-dehydro-16-carbomethoxy - 16-hydroxy-aspidospermidine N-oxide of Formula IV and treating the compound of Formula IV with a equimolar amount of triphenylphosphine or with another reducing agent for the N-oxide group in acidic environment to rearrange the product into a mixture of (-) - vincamine, 16-epi - vincamine and apo-vincamine, after which (-) - vincamine is recovered . Process according to claim 1, characterized in that the compound of formula IV and an equimolar amount of triphenylphosphine are dissolved in a low molecular weight liquid organic acid and preferably in acetic acid, which is cooled after two hours of boiling in a nitrogen atmosphere. in a large amount of water and washed with twice the amount of benzene or ether to remove the resulting triphenylphosphine oxide that the volatile organic phase is removed by decantation, then the acidic aqueous phase is then made alkaline to a pH of 10 and extracted with a