SK108494A3 - Process for the preparation of taxane derivatives - Google Patents

Abstract

Process for electrochemical preparation of taxane derivatives of general formula (I) based on a product of general formula (II). In general formula (I), Ar denotes an aryl radical, R1? is a benzoyl radical or R2?-O-CO- radical in which R2? is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical and R is a hydrogen atom of the acetyl radical. In general formula (II), Ar and R are defined as in general formula (I), R' is an acetyl or trichloro-2,2,2 ethoxycarbonyl radical and G1? is a trichloro-2,2,2 ethoxycarbonyl radical and G2? is a hydrogen atom. The products of general formula (I) have outstanding anti-tumoral properties.

Description

Technical field

The invention relates to a process for the preparation of taxane derivatives of the general formula

ococ ₆ h ₅ having remarkable antitumor and anti-leukemic properties. In the above formula, IR is hydrogen or acetyl,

R _x represents a benzoyl group or an R-O-CO- group in which R ₌ represents an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a bicycloalkyl group, a phenyl group or a nitrogen heterocyclic group and

Ar represents an aryl group.

In particular, in the above general formula

R is hydrogen or acetyl; and

R _x represents a benzoyl group or an R 6 -O-CO- group in which

R @ 1 represents a straight or branched alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 3 to 8 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkenyl group having 4 to 6 carbon atoms atoms or a bicycloalkyl group having 7 to 10 carbon atoms, these groups being optionally substituted with one or more substituents selected from the group consisting of halogen atoms, hydroxy, C1-C4 alkyloxy, dialkylamino, wherein each alkyl radical contains 1 up to 4 carbon atoms, piperidino, morpholino, 1-piperazinyl (optionally substituted at the 4-position with a C1-4 alkyl or phenylalkyl group in which the alkyl radical contains 1 to 4 carbon atoms), cyclo (C 3 -C 6) -alkyl, (C 4 -C 6) -cycloalkenylol, phenyl, cyano, cyrboxyl and alkyloxycarbonyl, in which the alkyl radical contains 1 to 4 carbon atoms, or a phenyl group optionally substituted by one or more substituents from the group consisting of C 1 -C 4 alkyl or C 1 -C 4 alkyloxy, or a saturated or unsaturated 5- or 6-membered nitrogen heterocyclic group optionally substituted by one or more C 1 -C 4 alkyl groups wherein the cycloalkyl a group, a cycloalkenyl group or a bicycloalkyl group may be optionally substituted by one or more alkyl groups containing 1 to 4 carbon atoms and

Ar represents a phenyl group or an alpha or beta-naphthyl group optionally substituted by one or more substituents selected from the group consisting of halogen atoms (fluorine atom, chlorine atom, bromine atom, iodine atom), alkyl group, aryl group, arylalkyl group, alkoxy group , alkylthio, aryloxy, aryl-thio, hydroxy, hydroxy-alkyl, mercapto, formyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino a group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a dialkylcarbamoyl group, a cyano group and a trifluoromethyl group, the alkyl groups and the alkyl radicals of the other groups having 1 to 4 carbon atoms and the aryl groups being phenyl or alpha or beta-naphthyl .

Of particular interest are compounds of formula I wherein R is hydrogen or acetyl, R 1 is benzoyl or tert. and Ar represents a phenyl group.

The products of formula (I) in which R is benzoyl correspond to taxol and 10-desacetyltaxol and the products of formula (I) in which R ^ represents tert. the butoxycarbonyl group corresponds to the products which form the subject of the European patent EP 0 253 738.

BACKGROUND OF THE INVENTION

According to the methods described, for example, in European patents EP 0 253 738, EP 0 336 840 and EP 0 336 841, the compounds of the general formula I are obtained after the replacement of the protecting groups R 1, G ₁ and G _{and the} compounds of the general formula II

O ₆ H ₅ wherein Ar and R 6 are as defined above, R 'represents an acetyl or hydroxy-protecting group selected from the group consisting of 2,2,2-trichloroethoxycarbonyl and a trialkylsilyl group in which each alkyl radical contains 1 to 5 3 carbon atoms, G _x represents a hydroxy function protecting group selected from the group consisting of 2,2,2-trichloroethoxycarbonyl and a trialkylsilyl group in which each alkyl radical contains 1 to 3 carbon atoms and G _and denotes a hydrogen atom or a hydroxy protecting group a function selected from the group consisting of methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (beta-trimethylsilylethoxy) methyl, tetrahydropyranyl, 2,2,2-trichloroethoxycarbonyl and 2,2,2-trichloroethoxymethyl, atoms.

Depending on the nature of the protecting groups, their replacement by hydrogen atoms may be carried out using zinc in the presence of a mineral or organic acid such as hydrochloric acid or acetic acid, optionally in solution in an aliphatic alcohol containing 1 to 3 carbon atoms, particularly if at least one of the protecting groups is

2,2,2-trichloroethoxycarbonyl, or using an acid such as hydrochloric acid in an aliphatic alcohol containing 1 to 3 carbon atoms at a temperature close to 0 ° C if at least one of the protecting groups is a trialkylsilyl group.

SUMMARY OF THE INVENTION

It has now been found - and this is the essence of the invention - that compounds of formula I can be obtained by electrolytic reduction of a compound of formula II in which Ar and R are as defined above, R 'is acetyl or 2,2,2-trichloroethoxycarbonyl group

G represents a 2,2,2-trichloroethoxycarbonyl group and represents a hydrogen atom, i. the compounds of formula (IIa) below.

Within the scope of the invention, the replacement of the protecting groups with hydroxyfunction by hydrogen atoms is carried out by electrolytic reduction according to the following reaction:

+ 2e (R 1 = CH ₃ CO) or + 4e (R 1 = Cl CCH OCO) + H * (I) + Cl '(or 2 Cl) + Cl ₂ C = CH ₂ (or 2 Cl ₂ C = CH ₂ ) + CO ₂ (or 2 CO ₂ ).

Said electrolytic reduction starting from a compound of formula (IIa) is carried out in an electrolyzer containing a carrier electrolyte in which a compound of formula (IIa) having a concentration of 0.1 to 40 g / l is dissolved.

The amount of electrical current necessary to effect reduction of the compound of formula IIa to the compound of formula I is 386 000 coulombs / mol when R 'is 2,2,2-trichlorotoxicarbonyl and 193 000 coulombs / mol when R' represents an acetyl group.

Preferably, said electrolytic reduction is carried out in a membrane electrolyzer.

According to an embodiment of the method according to the invention, said electrolytic reduction is carried out in an electrolyzer comprising a cathode, cathode zone, separation membrane, anode zone and anode, said parts of the electrolyzer having the following characteristics:

(a) the cathode consists of a current conducting material at which a reduction occurs at a potential higher than that of the solvent or one of the carrier electrolyte components, or at a potential where the reduction of the solvent or one of the carrier electrolyte components is not significant enough to interfere with the reduction the starting compound,

(b) the cathode zone comprises a catholyte consisting of a solution of a compound of formula IIa in an organic or aqueous-organic medium having a pH of between 4 and 7 and a carrier electrolyte;

c) the separation membrane consists of a porous material, such as a glass frit or porcelain plate, sheath or candle, or an ion-exchange membrane, preferably a cation-exchange membrane,

(d) the anode zone comprises an anolyte consisting preferably of the same solvent or solvent mixture and the same carrier electrolyte as used in the cathode zone; and

e) the anode is constituted by a current-conducting material, the nature of which is not essential in carrying out the process according to the invention.

Typically, the anode is a current conducting material which is not reactable under electrolysis conditions, for example in the form of a smooth platinum in the form of a block or arranged on a conductive support, or a graphite or vitreous carbon, while the cathode is an electric conductive material. is mercury, zinc, lead or glassy (glossy) carbon.

Preferably, the cathode is a mercury level.

The carrier electrolyte is an alkali metal salt or a quaternary ammonium salt such as sodium acetate in the presence of acetic acid or tetramethylammonium acetate dissolved in a solvent or aqueous-organic mixture. Typically, solvents are used which readily dissolve the compounds of formulas I and IIa and allow the compound of formula I to be readily isolated. Such solvents are, in particular, alcohols (methanol) and nitriles (acetonitrile).

The pH used must be compatible with the stability of the substrate and preferably equal to 4 to 6, and can be kept constant by the addition of acid during the electrolysis.

The nature of the membrane separating the anolyte from the catholyte is not critical to the process of the invention. It is therefore possible to use any membrane of known type, consisting of a porous material such as glass frit or porcelain, optionally in combination with a conductive gel limiting the diffusion of the reactants. Ion exchange membranes, preferably cation exchange membranes, may also be used. The membranes may be membranes of a homogeneous or heterogeneous type, which may optionally be mesh-reinforced. Preferably, non-expanding, non-buffering membranes are used and which are stable in the presence of the individual components of the anolyte and the catholyte.

In a preferred embodiment of the method according to the invention, the anode and the separation diaphragm are arranged in parallel planes, preferably vertically or horizontally when the cathode is formed by a mercury level. In addition, several elemental electrolytes may be coupled in the filter press method.

The temperature of the electrolytic bath is usually between 0 and 30 ° C.

Said electrolysis may be performed at a constant current density or at an inserted electrode potential. Preferably, the electrolysis is carried out at a constant current density of between 0.5 and 10 A / dm ² .

If the electrolysis is carried out at a controlled potential, the potential is set to about -1.4 V with respect to the reference calomel electrode.

The theoretical amount of electrical current used is 193,000 coulombs / mol when starting from a compound of formula IIa in which R 'is acetyl and 386 000 coulombs / mol when starting from a compound of formula IIa in wherein R 'is 2,2,2-trichloroethoxycarbonyl.

In a practical embodiment of the method according to the invention, the amount of electrical current consumed may be between 1.5 and 8 times the theoretical amount of electrical current.

Typically, the catholyte is circulated in a closed circuit, whereby said circulation is achieved, for example, by means of a pump. This circuit may additionally include auxiliary devices such as heat exchangers or expansion vessels. In particular, such an expansion vessel makes it possible to supply the catholyte with a compound of the formula IIa, while also allowing the catholyte to be withdrawn to isolate the compound of the formula I.

Also, the anolyte can be forced to circulate. In a preferred embodiment of the method of the invention, the circumference of the catholyte coincides with the circumference of the anolyte, allowing pressure balancing on either side of the separation membrane.

According to another specific embodiment of the method according to the invention, baffles are provided in the anode and cathode zones. These baffles serve both to eliminate the deformation of the ion exchange membrane and to avoid contact of the membrane with the electrodes. These baffles also serve to improve the homogeneity of the catholyte concentration.

In the absence of the septum, the rate of circulation of the catholyte in the cathode zone is usually greater than 10 cm / s, preferably greater than 50 cm / s. If a baffle is used, the apparent catholyte velocity (velocity in the cathode zone seemingly without baffle) is usually greater than 1 cm / s, preferably greater than 10 cm / s.

According to a further embodiment of the method according to the invention, the cell of the electrolyser can simply be a prism or cylindrical vessel made of a material which is inert to the components of the electrolyte. The vessel comprises a working electrode having a character similar to that defined for the first type of chamber. The shape of this working electrode is adapted to the shape of the container.

In general, any electrolytic cell comprising a cathode and an anode separated by one or more membranes providing ionic conductivity may be used, the arrangement of said elements being not critical in carrying out the method of the invention.

The product of formula (I) obtained by carrying out the process of the invention is separated using conventional methods.

Compounds of formula (IIa) can be obtained under the conditions described in European patent EP 0 253 738.

Compounds of formula (IIa) can thus be obtained by condensation of a beta-arylisoserine derivative of formula (III)

R _R NH? X-COOH of G _'2 wherein Ar and R are defined as above and G is a protective group _{of the} hydroxyl functional group, with a derivative of baccatin III or 10-deacetylbaccatin III of formula IV

wherein R 'a are as defined above, using the reaction conditions described in European patents EP 0 336 840 and EP 0 336 841 followed by the replacement of the protecting group G' with an hydrogen atom in an acidic medium.

Compounds of formula IIIa can also be obtained by condensation of an acid of formula V

(V) wherein Ar is as defined above, Boe means tert. butoxycarbonyl and R ₂ and R ₃ , which are the same or different, represent a hydrogen atom or a C 1 -C 4 alkyl group optionally substituted by one or more aryl groups (phenyl groups) or an aryl group (phenyl group) or R a _and and R ₃ together with the carbon atom to which they are attached form a 4- to 7-membered ring with a baccatin III or 10-deacetylbaccatin III derivative of formula IV to form a compound of formula VI

O-Gj

Ar

Ή

Boc-N. > 0

R ₂ 'r ₃ wherein Ar, Boe, R', G, R and R m

L JL (vi) / =

H = ÔCOCH ₃ oococ ₆ h ₅ are as defined above, which are treated with a mineral or organic acid, optionally in an alcohol, under conditions which have no effect on the protecting groups R 1 and G to form a compound of formula VII

(VII) in which Ar, R 'and have the above meanings, act on a benzoyl halide or a reactive derivative of formula VIII

R-O-CO-X which in general (VIII) in which R 6 is as defined above and X represents a halogen atom (fluorine atom, chlorine atom) or the radical -O-R or the radical -O-CO-OR 4, to form a compound of formula IIa.

The invention is explained in more detail below with reference to the following non-limiting examples, which are not to be construed as limiting the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Electrolytic reduction of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-trichloroethoxycarbonyloxy) -11-taxen-13alpha -yl-3-tert-butoxycarbonylamino-3-phenyl-2-hydroxypropionate is carried out in an electrolysis chamber having the following characteristics:

- the chamber consists of a 25 cm ³ glass container divided into two zones by a cation exchange membrane,

- the cathode consists of a mercury level with a useful area of 4 cm ² ,

the anode consists of a platinum network, and

the reference electrode is a calomel electrode.

10 cm ^{3 of a} solution containing: (2R, 3S) -4-acetoxy-2alpha-benzoyloxy5beta, 20-epoxy-1-hydroxy-9-oxo7beta, 10beta-bis- (2,2,2-trichloroethoxycarbonyloxy) are introduced into the cathode zone. -11-Taxen-13alpha-3-tert-butoxycarbonylamino-3-phenyl-2-hydroxypropionate Acetic acid

53.3 mg IM sodium acetate (CH ₃ COONa.3H ₃ 0) methanol make up to

0.1M cm ³

10 cm ^{3 of the} same substrate-free mixture is introduced into the anode zone.

After venting for 10 minutes by bubbling with a stream of argon, the cathode potential is set to 1,41.4 V relative to the reference electrode. The solution is electrolyzed for a time period of 30 coulombs. 9 cm ^{3 of} permuted water are then added to the separated electrolysate. After removal of the solvent under reduced pressure at a temperature below 35 ° C, the remaining aqueous phase is extracted 3 times with 20 cm ^{3 of} dichloromethane, then the organic phase is washed twice with 20 cm ^{3 of} sodium phosphate buffer (pH 7.4). After evaporation of the solvent under reduced pressure at a temperature below 35 ° C and separation by chromatography on a preparative thin layer of silica gel (layer thickness: 0.25 mm), eluting with a dichloromethane / methanol (94: 6 by volume) mixture, (2R, 3S) -4-Acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1,7beta, 10beta-trihydroxy-9-oxo-11-taxen-13alpha-yl-3-tert-butoxycarbonylamino-3- phenyl 2-hydroxypropionate (or taxotere) whose characteristics are the same as those of the product described in European patent EP 0 253 738.

Example 2

In this example, the substrate used in Example 1 is electrolyzed in a 25 cm ³ electrolysis chamber which does not contain a separation membrane and comprises:

- a cathode consisting of a mercury level with a useful surface area of 4 cm ² ,

- reference calomel electrode,

an anode formed by a platinum network.

10 cm ^{3 of a} solution containing:

substrate used in Example 1

51,5 mg acetic acid sodium acetate (CH ₃ COONa.3H ₂ 0) methanol make up to 100 ml

IM, IM 10 cm ³

After venting for 10 minutes by bubbling with a stream of argon, the cathode potential is set to 1,51.5 V from the reference electrode. The solution was electrolyzed for 50.4 coulombs. After treatment of the electrolysate under the conditions described in Example 1, a taxotere is obtained with a yield of 31%.

Example 3

In this example, the electrolysis chamber described in Example 1 is used.

10 cm ^{3 of a} solution containing:

substrate used in example 1 202.1 mg acetic acid IM sodium acetate (CH ₃ COONa.3H ₂ 0) 0.1 M methanol make up to 10 µm ³

10 cm ^{3 of the} same substrate-free mixture is introduced into the anode zone. After venting for 10 minutes by bubbling with a stream of argon, the current density is set to 1 A / dm ² . The solution was electrolyzed for the time required to pass 181 coulombs. 20 cm ^{3 of} permuted water are added to the separated electrolysate. After evaporation of the solvent under reduced pressure at a temperature below 35 ° C, the precipitate formed is filtered off on glass frit # 3. Rinsing with water and drying yielded 111.4 mg of a white solid, which was purified by chromatography on 50 g of silica gel (0.063-0.2 mm) as a 2 cm column, eluting with a mixture of dichloromethane and methanol in a 93: 3 volume ratio, collecting fractions of about 10 cm ³ . Fractions 14 to 40 are combined and concentrated under reduced pressure (0.27 kPa) below 35 ° C. A taxotere is obtained with a yield of 43%.

Example 4

In the cathode zone of a 25 cm ³ H-shaped electrolysis chamber divided into two zones by a cation exchange membrane and comprising:

a glassy carbon cathode with a useful surface area of 4,5 cm ^2, and

- a platinum anode, insert 20 cm ^{3 of a} solution containing:

substrate used in Example 1 205,5 mg acetic acid IM tetraethylammonium acetate 0, IM acetonitrile to 20 cm ³

20 cm ^{3 of the} same substrate-free mixture is introduced into the anode zone. After venting for 10 minutes by bubbling with a stream of argon, the current intensity is set to 40 mA, then reduced to 10 mA (0.9 A / dm ² ) after passing 103 coulombs. · The solution is electrolyzed for the time required to pass 150 coulombs. The electrolysate is freed from the solvent by evaporation under reduced pressure at a temperature below 35 ° C. 20 cm @ ^{3 of} water are added to the residue and the mixture is extracted three times with 20 cm @ ^{3 of} dichloromethane. After drying the organic phase over magnesium chloride, 146 mg of crude product is isolated, which is purified by chromatography under the conditions described in Example 3. A taxotere is obtained in a yield of 41%.

Claims (10)

PATENT CLAIMS A process for the preparation of a taxane derivative of the formula I wherein R represents a hydrogen atom or an acetyl group, R represents a benzoyl group or an R-O-CO- group in which R 5 represents an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group a group, a bicycloalkyl group, a phenyl group or a nitrogen-containing heterocyclic group and Ar represents an aryl group, characterized in that an electrolytic reduction of the compound of the formula IIa is carried out R _r NH O Ar OH (IIa) in which Ar and R are as defined above, R is acetyl or 2,2,2-trichloroethoxycarbonyl. Second 5. The process of claim 1 wherein the electrolyte is an alkali metal salt or a quaternary ammonium salt soluble in a solvent or aqueous-organic mixture. Process according to claim 2, characterized in that a solvent selected from the group consisting of alcohols and nitriles is used. Method according to claim 3, characterized in that. methanol or acetonitrile is used as solvent. * Method according to one of claims 1 to 4, characterized in that the electrolysis is carried out in an electrolyzer comprising a cathode of a material selected from the group consisting of mercury, zinc, lead and glassy carbon and an anode of a material selected from the group consisting of platinum, graphite and glassy carbon. Method according to one of Claims 1 to 4, characterized in that the electrolysis is carried out in an electrolyser, preferably a membrane electrolyser. . Method according to claim 6, characterized in that the membrane is a porous material or a cation exchange membrane. 8. The method of claiming potential. The electrolysis is carried out at a controlled rate Method according to one of Claims 1 to 7, characterized in that the electrolysis is carried out under a current load on the electrodes. The process of claim 1 for the preparation of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1,7beta, 10beta-trihydroxy-9oxo-11-taxen-13alpha-yl-3-tert-butoxycarbonylamino- 3-phenyl-2-hydroxypropionate or taxotere.