LU84640A1 - NEW PROCESS FOR OBTAINING VINCRISTINE AND VINCRISTINE SULFATE - Google Patents

Abstract

1. Process for the preparation of vincristine or its addition salts from vinblastine characterized in that vinblastine is treated with permanganate ion in acid medium in an inert solvent consisting of toluene or dichloromethane, the permanganate ion being solubilized by action of a macrocyclic polyether on the potassium permanganate or in the state of a quaternary ammonium salt soluble in the said inert solvant, and in that the reaction medium is maintained at a temperature of between -40 degrees C and -75 degrees C.

Description

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! NEW PROCESS FOR BTENING OF THE. VEJCRISTIKE

AND VINCRISTINE SULFATE

The present invention relates to a new process for obtaining vincristine by selective oxidation of the ethyl ethyl group of wine. , * 1 blastine.

i ί ij Vincristine is an fcis-indole alkaloid corresponding to the formula i] I in which R represents a forcyl group.

• i. OH

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MeO, C \! . CH „0 [J‘ ^ n- (I)> 1 1 R CrsCH, - j i.

vincristine is used in anticancer chemotherapy, in particular for the treatment of certain declared laucsr_.es.

. This alkaloid is obtained mainly by extrac-'or. 2 start from; leaves this Catiarar.thus Roseus (patent these States · ° ~ 3 205 22 h where there is acxxrpagr.ë other alkaloids bis-incm '' in particular Vinblastine. Vinblastine (I, p _ o ^ t oetendin- present at a concentration much higher than this; i5 ~ s vincristine and therefore constitutes a precursor of choice for the hérysv-th ^ se of cetta; last.

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j! 1 Several processes for the production of vincristine from vinblastina have been disclosed, all of which include: I the following patents or applications for this patent: • i - | | a) beige patent 793,337 (Sichter Geceon) which describes a method for the oxidation of Vinblastine to vincristine by J a mixture of erratic acid, acetic acid and acetone.

I b) Belgian patent S23.560 (Richter Gedeon): the oxidation is carried out by oxygen in ferric acid and in the presence f of a platinum-based catalyst at ambient temperature.

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lzc) applies for this patent: European 18 231 (Richter éedeen}: ί the oxidation is carried out by chronic acid or an alkali metal cichrarace in the presence of acetic anhydride 1 and optionally ethanol. 01 d, ii ~ crcaniaue solvent v- immiscible with water.

i l d) apply for this European patent n ° 37.289 (Ξ11 Lilly):! *! ! the oxidation is carried out with per (II) iron chlorate in the presence of hydrogen perexide and tri acetone

In addition, European patent application 37.292 describes a process for the oxidation of Vinblastine base with a? Cr907 in the presence of sulfuric acid like titraiyerefuranne.

This reaction, carried out at -5 ° C., is carried out with a yield of 80-92% calculated by assay.

'i the observed rerderer.ts or the purity of the products obtained characterizing ant the processes described above ccrstrtuent ï, these imoortant disadvantages. A frequently shoddy secretary product! ;

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, î ':, is the N-cém.éthvl Vinblastine which must then be reforiavler

I to get vincristine.

The process of the present invention nernet that produce vincristine in a simple way in significant amount! and at a decreed of purity which little or no attenuates this ourification - additional cation by recrystallization or chronato- | spelling.

£ | I The oxidation reagent used is the permanganate ion J solubilized in an aromatic solvent or a solvent! Chlorinated orcanirrue. An alternative is to immobilize the permanganate anion on a resin / par ;; Example an oolvm & re of the Dolvstvr ^ head comprising ammonium croups.

t i ’The solubilization can be carried out by the action of a ** i; acent complexing tvoe crown ether ("crovn-ether") j on Dermancanate this potassium.

"The permanganate anion can also be dissolved by preparing an ammonium or phoshonium salt. Quaternary; corresponding which is soluble in an organic solvent, in particular an organic chlorinated solvent such as dichioromethane. For this purpose, this preference will be used benzvltriëthvlammonium oermancanate ;.

• h: ¾ Obtaining vincristine ~ from this Vinblastine using i a salt this Permanganate is unexpected since the oermancanate this potassium used in acetone oxvde certain derivatives of Vinblastine at the level of the velbanamine part of the molecule (Kutnev, Balsevich and '»» orth, Heterocvcles, 11, 69, 197P). The N-methyl group that the Vindoline part remains intact.

/ The formation of a rump ΐΤ-ΓΗΟ on a bis-inccle skeleton ^ had crust this Vinblastine, using a salt this per- 4, ·! manganate has not been reported.

i m J According to one mode of the process of the present invention, the; | vinblastine, preferably in the form of this sulfate, J is treated in the presence of a crganic acid such as acetic acid, with an excess of permanganate, this dissolved potassium; in a chlorinated oraanicrue solvent or toluene in the presence || of "l ^ -crown-ô" ether or the corresponding cibenzo- or cicyclohexyl-! $ derivatives. The reaction is carried out at a temperature iii: "between -40 ° C and - ^ 5 ° C and is advantageously followed ί by chromatography on a thin layer. The reaction grounds * generally vary from 5 minutes to 3 hours.

Potassium permanganate is this preference dissolved in dichloromethane and the oxidation reaction is.-I. "then performed * -70 ° f !.

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The solubility of potassium permanaanate is in fact substantially increased in the presence of a macrocyclic pclvether such as "18-crown-5" ether (1,4,7,10,13,16-hexacxacvclooctadecane) or the dibenzo- or derivative corresponding dieveie-hexvl.

The reaction mixture is then simultaneously treated with a soft reducer and alkalized. For this purpose, an aqueous solution is preferably used, this sodium bisulfite 1 st of the ammonia.

__ your organ phase is separated and the aqueous phase is • extracted several times with methylene chloride. The combined organic phases are concentrated under vacuum to provide a residue comprising 80-85% of vincristine base / ie a yield of 90-95%.

<:>! '· / __ 5 jî: 1 ij Alternatively, the! 1 ij * reaction medium may have to be extracted after reduction without proceeding with simultaneous alkalization. The acidic 1 acid solution is then extracted with dichloronethar. This .ij route constitutes an original process for the purification of the vincristine formed in the reaction medium.

•! According to another embodiment of the present invention, vincristine is obtained by oxidation of vinblasti ne by the action of a quaternary ammonium permanganate. The ammonium cation is preferably arouoe benzvltriéthvlammonium or benzvl-; - trirrethvl ammonium. (see e.g. Ancew. Chem., Intern.Ed.

i l ?, 1 ^ 0, 1 ^ 4). The reaction is carried out in 2 to 6 h at -60 ° C in a mixture of dichloromethane and acid! clacial acetaria. After treatment with a mild reducing agent in an aqueous medium, the resulting acid solution i is extracted because the dichloromethane is i.

nn-'se orçaniQue is alkalized by ± avage ‘aqueous solution basic and concentrated. The solvated vincristine is isolated with a yield greater than 90%.

Γ-years in most cases, vincristine thus obtained! can be directly transformed into an addition salt - of organic or inorganic acid, preferably an acharmically acceptable salt.

In particular, vincristine sulphate is obtained by adding ce to a crude or recrystallized base vincristine solution because of ethanol, dissolved in an anhydrous methviene chloride-ethancl mixture, partial removal of the methylene chloride under vacuum and crystallization.

The sulfate this vincristine thus obtained has a decre »of purity sufficient to be used as a medicament, J in particular in the form of this injectable solute.

il 6 'il ILoxidation process described in the present invention * can also be apolicrué to other bis-i indolic alkaloids having an aroune N-rethvle analoaue à la% -

vindoline. Leurosidine or deox ^ -4'Vinblastin A or B

jj ’can thus be transformed into a corresponding N-formvl derivative. The method can also be used to obtain N-formvl theirosin yes is particularly '! 4 active as an anti-tumor agent. Optionally, the: | new procurement process will be added to derivatives l-: i! . bis-indoliaues of the Vinblastine tvpe cssacétvlés in position 0-4, the hvdroxvle orouD remaining inert in || the oxvdation conditions used. This method * can in particular be used nour obtaining this n-formvl derivative of Vinblastine conjugated with amino acids or oeptices, p. e. N-vmblastinoyl-2 3 ethvl leucinate.

!; EXAMPLES

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Vincristine formation by oxidation at EMnC „ce VLB.

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A solution of 2.73 g of this Vinblastine sulfate in 330 ml of methylene chloride and 42 ml of acetic acid is sparged with argon for 30 minutes at room temperature and then cooled to -7 ° C.

Cr. add solu.tror to crust. ce 1,0 / g es ΕΜηΟ „

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in 125 ml of methylene chloride and 2.22 g of 1,4,7,10,13,16-i hsxacxacycioactadecane (iS-crown — 6). The reaction is followed ’i’ and controlled by TLC (Silica plate - elutior. Einer SO - y ’methane! 20).

The reaction medium is then poured onto a cooled and stirred mixture (pasty consistency) of 220 ml of aqueous solution of | 5% sodium bisulphite and 110 ml of 14 N arrriaque.

! j i | ; I The possible emulsion due to the presence of this dioxide this manganese i | is treated by filtration of the total mixture on earth of diatrates.

11 The two clear phases are decanted and the aqueous phase is 1 *.

ί j exhausted by methylene chloride. The extracts are gathered, l | dried on higSQ, and evaporated to dryness (Weight: 2.93 g).

k <! i i The residue is dosed at 83% vincristine base, ie a yield * of 56%.

•} Vincristine base is obtained by crystallization of the residue in ethanol and is identical to an authentic sample! this reference (mass sector, UV sector, BMI ^ H spectrum).

he d

Ïïj! Sulfate:

Vincristine base is dissolved in a mixture of CH ^ Cl ^ and ethanol (60:40) * The pH is adjusted to 4.00 by adding a 1.84% solution of ILSCb in anhydrous ethanol .

. / * 4 | The solvent is partially removed by distillation in an empty sense and the sulfate slowly crystallizes by stirring the solution at room temperature.

i ί * χ— "" i.! / / * fi 1 11 8 i I 1 - formation of vincristine because oxvdation of jVinblastine in the presence of benzvl-iang triethv1ammonium permanganate.

j ff j In a 4 L flask, place 20 g of sulphate

Vinblastine in 1.6 L this dichloroethane. <~> n adds 360 ml of dry acetinic acid yes solubilizes Vinblastine. Cooled under an argon atmosphere at -60 ° C.

A 27.68 σ solution of benzvltri-ethvlammoniun demancranate in 1.6 L of dichloromêthar is prepared. This solution is filtered on paper so i, | to eliminate a possible precipitate of dioxin from this manganese.

| i Add the drop by drop oxvdanie solution; . without exceeding -60 ° C. The addition is carried out in 3 hours.

A 3.9 cc solution of 5% sodium bisulfite is cooled to a pasty state. Or. Transfers, under pressure> c 'arcor. the reaction recovery in the bisuroite solution yes is mechanically activated. The mixture is left to return to ambient temperature and the aqueous phase is exhausted with dichlorc-methane (3.7 L initially, then 3 L, then twice 2L).

The combined organic phases are made alkaline by adding this 7 L to this sodium bicarbonate at 80 g / L. The dichloroethane is then £ v & r> oré under vacuum. This gives 16.47 ç this crude vincristine. After drying under vacuum for 17 hours at room temperature, we believe 15.17 g of • vincristine of higher curity? 92%.

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Claims (5)

3. Method according to claim 1 characterized in that i · !,; oue the ion Dermanaanate is solubilized in the form ce \ ataternary ammonium salt soluble in a chlorinated organic solvent. 4. Method according to claim 1 characterized en-.ee! that the acid used is the active acid. 5. Method according to claims 1 * 4 characterized in that the solvent used is dichloromenhane. vs'. Process according to claims 1% 5, characterized in that the temperature of the reaction medium is maintained at approximately - 70 ° C. 7. Method according to claim 7 characterized in that the ammonium salt is benzvltri-- permanganate s ét.hvl ammonium. w% 4 v 10 $ \ î | “B. Process according to claim 1, in which the reaction medium after permanent treatment * | The anate is treated with an auous solution of bisulfite. . 9. Method according to claims 1 3. B in ’leouel before isolating vincristine this way i | Classically, the aqueous reaction medium resulting from the addition of this bisulfite solution is extracted with dichloromethane. 10. Products obtained by adding the orocécé to one; cruel designed of claims 1 to 9. / ^^ -----__ ', i i: “i 1 ti r;