NO331813B1 - Process for Preparation of 4,10beta-diacetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1,13alpha-dihydroxy-9-oxo-19-norcyclopropa [G] tax-11-one and process of preparing an intermediate. - Google Patents

Abstract

This invention relates to a process for the preparation of 4,10β-diacetoxy-2α-benzoyloxy-5β, 20-epoxy-1,13α-dihydroxy-9-oxo-19-norcyclopropa [g] tax-11-ene from 4-acetoxy-2α-benzoyloxy - 5β, 20-epoxy-1,13α-dihydroxy-9-oxo-7β-trifluoromethylisulfonyloxy-taxa-11ene by reaction with a molecular sieve in sulfolane.

Description

The present invention relates to a new method for the production of taxoids with the general formula:

In the general formula (I) represents

Ar is an aryl radical,

R a hydrogen atom or an acetyl, (C3-C6) alkoxyacetyl or (C1-C4) alkyl radical,

Ri is a benzoyl radical or an R 2 -O-CO radical wherein R 2 represents a straight or branched alkyl radical containing 1 to 8 carbon atoms.

Ar preferably represents a phenyl radical optionally substituted with one or more atoms or radicals selected from halogen atoms (fluorine, chlorine, bromine or iodine) and alkyl, alkoxy, alkylthio, cyano, nitro and trifluoromethyl radicals, where it is understood that alkyl radicals and the alkyl part until the radicals contain 1 to 4 carbon atoms, or else Ar represents an aromatic heterocyclic radical having 5 ring members and containing one or more identical or different atoms selected from nitrogen, oxygen or sulfur atoms.

More particularly, Ar represents a phenyl, 2- or 3-thienyl or 2- or 3-furyl radical.

Even more particularly, Ar represents a phenyl radical optionally substituted with a chlorine or fluorine atom or with an alkyl (methyl), alkoxy (methoxy) or 2- or 3-thienyl or 2- or 3-furyl radical.

Even more preferred is the product of general formula (I) in which Ar represents a phenyl radical, Ri represents a tert-butoxycarbonyl radical and R represents an acetyl radical.

Mention can be made, among the methods known per today for the production of compounds with formula (I), patent EP 0 673 372, which describes a method starting from 10-deacetylbaccatin III, which in the first step consists of a protection of 10-deacetylbaccatin III in the 7-position, in a second step in acetylation in the 10-position, in a third step in deprotection of the 7-position, in a fourth step in carrying out a trifluoromethanesulfonylation (or triflation) in the 7-position, in a fifth step in carrying out a cyclopropylation in the 7- 8-position, and then in a penultimate step, in attaching the side chain in the 13-position and, finally, in a final step, in deprotection of the side chain. The step of cyclopropylation in the 7-8 position is carried out in the presence of either an alkali metal halide (sodium iodide, potassium fluoride) or alkali metal azide (sodium azide) or of a quaternary ammonium salt or, finally, an alkali metal phosphate.

It has subsequently become clear, as described in the patents published under numbers WO 95/33736, WO 95/33737 and WO 96/32387, that the presence of alkali metal azide or halide (sodium iodide, potassium fluoride) was not essential and that an additive such as molecular sieve under presence of sodium fluoride) was effective. The solvent used in these three patent applications consisted of a mixture of acetonitrile and tetrahydrofuran.

It is also known fira the publication of Johnson, Nidy, Dobrowolski, Gebhard, Qualls, Wicnienski and Kelly which was published in Tetrahedron Letters, vol. 35, No. 43, pp. 7893-7896, 1994, that 7-O-triflate can be converted to 7(5,8p-methanotaxane in the presence of a large excess of silica gel; where the excess is 60 times the weight of the 7-O-triflate derivative , which is industrially unusable.

According to the present invention, the method described in the three above-mentioned patents has been improved by using sulfolane.

The compound of the following formula (I)

in which

Ar represents an aryl radical,

R represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl radical,

R 1 represents a benzoyl radical or an R 2 -O-CO radical in which R 2 represents a straight or branched alkyl radical consisting of 1 to 8 carbon atoms,

is prepared by a process which consists of bringing the compound of formula (II)

wherein R' is a protecting group for the hydroxyl functional group when R represents hydrogen in formula (I) or one of the groups indicated for R, in contact with a weak base selected from molecular sieves, and then successively or beforehand, in coupling of a precursor to the side chain and, finally, in deprotecting the optionally protected hydroxyl functional groups, which involves carrying out the cyclopropanation reaction in sulfolane. The present invention also relates to a method for producing an intermediate of general formula (III)

in which R' has the same meaning as in formula (II) above, by bringing the derivative of general formula (II) into contact with a molecular sieve, which is carried out in sulfolane.

In a preferred embodiment, the cyclopropylation reaction is carried out in sulfolane which includes between 2 and 5% by weight of water. The presence of water makes it possible to convert the derivative of formula (IV) below, a by-product produced during the cyclopropanation, into the derivative of formula (V); the separation of the derivative of formula (III) and of the derivative of formula (IV) is difficult, while the separation of the derivative of formula (V) from the derivative of formula (III) is easier.

For better implementation of the present invention, it is preferred to operate with an amount of water of approx. 4% by weight with respect to sulfolane. The reaction temperature is particularly between 20°C and the boiling point of the reaction mixture.

The addition is carried out with approx. 25 to 100 wt% molecular sieve to the substrate. Regarding the reaction conditions, the reaction is generally carried out at between 20oC and the boiling point of the solvent for one to several hours.

According to a better method for implementing the invention, hydrated sulfolane (approx. 4% by weight water) will be used as reaction solvent in the presence of 100% by weight 4 Å molecular sieve as activated powder with respect to the substrate. In this case, the reaction will be carried out at a temperature in the region of 60°C until the substrate has been completely converted.

The product of formula (II) in which R' represents a protecting group for the hydroxyl functional group or an acetyl, alkoxyacetyl or alkyl radical can be obtained by reaction with a derivative of trifluoromethanesulfonic acid, such as the anhydride or chloride, with baccatin III or 10-deacetylbaccatin III protected in its 10-position with a protecting group, such as trichloroethoxycarbonyl in particular.

In general, the reaction with a derivative of trifluoromethanesulfonic acid is carried out in an inert organic solvent (aliphatic hydrocarbons, optionally halogenated, or aromatic hydrocarbons) in the presence of an organic base, such as a tertiary aliphatic amine (triethylamine) or pyridine, at a temperature of between - 50 and +20°C.

According to a better method for implementing the invention, where one of the preferred compounds of formula (III) where R represents an acetyl group is prepared from the compound of formula (II) where R has the same meaning,

after reaction between the compound of formula (II) and the molecular sieve:

the impure product is isolated by a series of treatments, such as the possible addition of a solvent, such as ethyl acetate, removal of the insoluble materials by filtration, concentration of the reaction medium and then crystallization by the addition of solvents that induce solubility, such as in particular water or toluene ,

then either the impure product is purified by recrystallization from a solvent or from a solvent mixture, such as methanol, methanol as a mixture with diisopropyl ether or toluene, sulfolane as a mixture with toluene, or methylene chloride as a mixture with diisopropyl ether, or ethyl acetate as a mixture with diisopropyl ether,

or the impure product is purified by chromatography on silica gel, eluted with methylene chloride as a mixture with ethyl acetate, methanol or acetonitrile.

Preferably, the medium will be treated by adding ethyl acetate, filtering the molecular sieve, concentrating under reduced pressure and precipitation by adding water with seeding.

Preferably, the impure product will be purified by crystallization from an ethyl acetate/diisopropyl ether mixture at a ratio of between 50/50 v/v and 10/90 v/v and preferably 25/75.

The product of formula (III) which is obtained is then or beforehand coupled according to a method known per se with a precursor to the side chain selected from (3-phenylisoserine protected in the 2'-position, as described in patent EP 336 840, oxazolidines, such as those specifically described in patents EP 595 370, EP 663 906, EP 663 907, EP 663 908, EP 666 857 and EP 669 915, or β-lactams, such as those specifically described in the following patents EP 400 971, US 5,254,580 and US 5,466,834.

The following examples illustrate the present invention.

EXAMPLE 1

2.0 g of 4,10(3-diacetoxy-2a-benzoyloxy-5(5,20-epoxy-1,13a-dihydroxy-9-oxo-7(}(trifluoromethylsulfonyloxy)tax-1l-ene with a purity of 92%, 2.02 g of 4 Å molecular sieve as activated powder and 1.0 g of sodium chloride are added to 14 ml of sulfolane in a 50 ml three-necked flask and the mixture is heated to 60<*>0 for about 4 hours. The reaction medium is cooled to ambient temperature and then filtered. The insoluble materials are washed 3 times with 50 mL of ethyl acetate and the organic phases are combined. 4,10(5-Diacetoxy-2a-

benzoyloxy-5 (5,20-epoxy-1,13a-dihydroxy-9-oxo-19-norcyclopropa[g]tax-11 -ene (I) the solution thus obtained is quantitatively determined by HPLC with respect to a standard (1 .29 g, yield 88%).

Comparative examples with different solvents

The results are shown in the following table:

EXAMPLE 2

60.0 g of 4,10(}-diacetoxy-2a-benzoyloxy-p,20-epoxy-1,13a-dihydroxy-9-oxo-7(5-(trifluoromethylsulfonyloxy)tax-1 l-ene with a purity of 89 .8% by weight, 60 g 4 Angstrom molecular sieve as activated powder and 9.6 ml of water are added to 240 g of sulfolane in a 500 ml three-necked flask and the mixture is heated with stirring to 60°C for about 4 hours. The reaction medium is cooled to 40<*C and 200 ml of ethyl acetate are added. The suspension is filtered through a bed of Dicalite and the insoluble material is washed 4 times with 50 ml of ethyl acetate. The organic phases are combined and 4,10(5-diacetoxy-2a-benzoyloxy-5(} ,20-epoxy-1,13a-dihydroxy-9-oxo-19-norcyclopropa[g]tax-1 l-ene The solution thus obtained is quantitatively determined by HPLC with respect to a standard (37.5 g, yield 88%) A fraction of the solution (152 g) is concentrated under a pressure of less than 15 mm Hg at 45° C. for about 45 minutes and the obtained concentrate (75.2 g) is stirred at 40° C. 59.2 ml of demineralized water is added within an hour to the solution and d then seeding is carried out at 40°C with 100 mg of 4,10(5-diacetoxy-2a-benzoyloxy-5 (5,20-epoxy-1,13a-dihydroxy-9-oxo-19-norcyclopropa[g]tax-11 -one. The medium is cooled to ambient temperature within 2 hours and 30 minutes and then 80.3 g of demineralized water is again added within 1 hour. The suspension is then cooled to 0-4°C during approx. 1 hour and 30 minutes. The product is filtered off, washed 3 times with 33 ml of demineralized water and dried under reduced pressure at 45°C for 16 hours. 12.65 g of impure product is thus obtained, where the product has a purity of 70.8% by weight quantitatively determined by HPLC (yield 83%).

12.5 g of impure product are added to a 100 ml round-bottomed flask and dissolved in 25 ml of methanol at 55 °C. The reaction medium is cooled to 35 °C and then seeded with a few mg of 4,10p-diacetoxy-2a-benzoyloxy-5 (5,20-epoxy-1,13a-dihydroxy-9-oxo-19-norcyclopropa[g]tax-1 l-en. The suspension is then cooled to ambient temperature and then to O^C over about 3 hours. After filtration, the product is washed twice with 5 ml of diisopropyl ether and then dried under reduced pressure at 45<*>C for 16 hours 7.1 g of pure product is thus obtained, where the product has a purity of 97.7% by weight quantitatively determined by HPLC (recrystallization yield of 66%).

EXAMPLES 3 TO 5

Example 2 is repeated for the impure product, a variable amount of water is added to the sulfolane.

The impurity named ETHYLENE-2 is difficult to separate from (III) by silica chromatography or crystallization; unlike this, the impurity named ETHYLENE-1 is easy to remove with the same techniques.

EXAMPLE 6 - Purification by crystallization from methanol

58 g of 4,10p-diacetoxy-2a-benzoyloxy-p,20-epoxy-1,13a-dihydroxy-9-oxo-7p-(trifluoromethylsulfonyloxy)tax-1 l-ene with a purity of 92%, 58 g 4 angstrom molecular sieve as activated powder and 29 g of sodium chloride are added to 580 ml of ethyl acetate in a 2-litre glass reactor and the mixture is heated with stirring to between 55 and 65 *C for approx. 46 hours. The reaction medium is cooled to ambient temperature and filtered through a Clarcel bed and the insoluble material is washed twice with 116 ml of ethyl acetate. The organic phases are combined and the 4,10(5-diacetoxy-2a-benzoyloxy-5(5,20-epoxy-1,13a-dihydroxy-9-oxo-19-norcyclopropa[g]tax-ll-ene) solution thus obtained is washed with an aqueous sodium bicarbonate solution (17.4 g in 290 ml of water) and then twice with 290 ml of water.The reaction medium is concentrated to a volume of about 200 ml under reduced pressure at a temperature of less than 40°C and 825 ml of methanol is added. Solvent change is carried out by distillation under reduced pressure at a temperature of less than 40°C by addition of methanol (1145 ml total) and then the solution is cooled to ambient temperature Crystallization is initiated with 0.21 g of 4,10p-diacetoxy-2a- benzoyloxy-5 (5,20-epoxy-1,13a-dihydroxy-9-oxo-19-norcyclopropa[g]tax-1 l-ene and then the suspension is cooled to 0°C over about 1 hour and 30 minutes The suspension is filtered and the product is washed twice with 116 ml of diisopropyl ether. After drying at ambient temperature to constant weight, 25 g of prod ukt obtained (yield 55%), where the product is examined at 94% by weight with HPLC quantitative determination (> 99% in relation to areal internal normalization).

EXAMPLE 7 - Purification by chromatography

4.9 g of impure 4,10(5-diacetoxy-2a-benzoyloxy-5(5,20-epoxy-1,13a-dihydroxy-9-oxo-19-norcyclopropa[g]tax-1 l-ene by an HPLC purity of 93.9% (internal normalization of the areas) and examined at 65.5% by weight, purified by chromatography with 250 g of silica gel, elution carried out with a mixture of methylene chloride and ethyl acetate (v/v: 75/25). containing the product are combined and concentrated under reduced pressure. The solution obtained (241 g) is examined at 1.3% v/v by HPLC quantitative determination. The purity by HPLC is 99.4% (purification yield of 97%).

EXAMPLE 8 - Purification by crystallization from diisopropyl ether (DIPE)

23 g of impure 4,10p-diacetoxy-2a-benzoyloxy-5|5,20-epoxy-1,13a-dihydroxy-9-oxo-19-norcyclopropa[g]tax-1 l-ene with a purity of 91% at HPLC and examination at 77.5% by weight dissolve in approx. 640 ml of ethyl acetate and the organic phase obtained is washed twice with 255 ml of water. The solution is then concentrated under reduced pressure at approx. 30°C to a residual volume of approx. 74 ml. 222 ml of diisopropyl ether is then added to the solution over 4 to 7 hours at ambient temperature and then the resulting suspension is cooled to 2°C. The suspension is cooled and the product cake is washed with 36 ml of diisopropyl ether. After drying under reduced pressure at 25°C, 17.6 g of purified 4,10p-diacetoxy-2a-benzoyloxy-5P,20-epoxy-1,13a-dihydroxy-9-oxo-19-norcyclopropa[g]tax -l l-en obtained, which product has a purity of approx. 97% and examined at 89.3% by weight (yield 88%).

Example 8 is repeated with different recrystallization solvents.

Claims (13)

1. Process for the preparation of the compound of formula (I) in which Ar represents an aryl radical, R represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl radical, R 1 represents a benzoyl radical or an R 2 -O-CO radical in which R 2 represents a straight or branched alkyl radical containing 1 to 8 carbon atoms, by a method which consists in bringing the compound of formula (II) wherein R' is a protecting group for the hydroxyl functional group when R represents hydrogen in formula (I) or one of the groups indicated for R, in contact with a weak base selected from molecular sieves, and then successively or beforehand, in coupling of a precursor to the side chain and, finally, in deprotecting the optionally protected hydroxyl functional groups, characterized in that it involves carrying out the cyclopropanation reaction in sulfolane. 2. Method according to claim 1, characterized in that R is an acetyl radical, Ri is a tert-butoxycarbonyl radical and Ar is a phenyl radical. Method according to claim 1, characterized in that the reaction is carried out in the presence of 4 Å molecular sieve as activated powder. 4. Method according to claim log3, characterized in that a weight proportion of the molecular sieve is used in relation to the compound with formula (II) of approx. 100% by weight. 5. Method according to claims 1 to 4, characterized in that the sulfolane includes 2 to 5% by weight of water. 6. Method according to claim 5, characterized in that the sulfolane includes approx. 4% water. 7. Process according to claims 1 to 6, characterized in that the reaction temperature is between 20°C and the boiling point of the solvent. 8. Method according to claim 6, characterized in that the reaction temperature is approx. 60°C. 9. Process according to claim 1, characterized in that the impure product is isolated by adding ethyl acetate to the reaction medium, filtering the molecular sieve, concentrating the reaction medium and then crystallization by adding water. 10. Process according to claim 9, characterized in that, after isolation, the impure product is purified by recrystallization from a solvent or a solvent mixture selected from methanol, methanol as a mixture with diisopropyl ether, methanol as a mixture with toluene, sulfolane as a mixture with toluene, methylene chloride as a mixture with diisopropyl ether, or ethyl acetate as a mixture with diisopropyl ether. 11. Method according to claim 10, characterized in that the impure product is purified with a mixture of ethyl acetate and isopropyl ether according to a ratio of approx. 25/75 w/w. 12. Method according to claim 1, characterized in that the precursor to the side chain is selected from derivatives of (}-phenylisoserine protected in the 2'-position, oxazolidines or β-lactams. 13. Process for the preparation of an intermediate of general formula (III) wherein R' has the same meaning as in formula (II) according to claim 1, by bringing a derivative of general formula (II) in contact with a molecular sieve, characterized in that it is carried out in sulfolane.