AU2004230302A1 - Process for the preparation of 4,10B-diacetoxy-2a-benzoyloxy-5B,20-epoxy-1,13a-dihydroxy-9-oxo-19-norcyclopropa[g]TAX-11-ene - Google Patents

Description

IN THE MATTER OF an Australian Application corresponding to PCT Application PCT/FR2004/000901 I, John Neil Albert SWEENEY BSc, PhD, Dip. Trans. IoL, translator to RWS Group Ltd, of Europa House, Marsham Way, Gerrards Cross, Buckinghamshire, England, do solemnly and sincerely declare that I am conversant with the English and French languages and am a competent translator thereof, and that to the best of my knowledge and belief the following is a true and correct translation of the PCT Application filed under No. PCT/FR2004/000901. Date: 30 September 2005 J. N. A. SWEENEY For and on behalf of RWS Group Ltd WO 2004/092151 - 1 - PCT/FR2004/000901 METHOD FOR PRODUCTION OF 4,10P-DIACETOXY-2a-BENZOYLOXY 51,20-EPOXY-1,13a-DIHYDROXY-9-OXO-19 NORCYCLOPROPA [g] TAX-ll-ENE 5 The present invention relates to a novel process for the preparation of taxoids of general formula: R-O

R

1 -NH Ar O (I OH H HO OCOCH 3

DCOC

6

H

5 10 In the general formula (I), Ar represents an aryl radical, R represents a hydrogen atom or an acetyl, (C3-C6) alkoxyacetyl or (C1-C4) alkyl radical, Ri represents a benzoyl radical or an R 2 -0-CO- radical 15 in which R 2 represents a straight or branched alkyl radical comprising 1 to 8 carbon atoms. Preferably, Ar represents a phenyl radical optionally substituted by one or more atoms or radicals chosen 20 from halogen atoms (fluorine, chlorine, bromine or iodine) and alkyl, alkoxy, alkylthio, cyano, nitro and trifluoromethyl radicals, it being understood that the alkyl radicals and the alkyl portions of the radicals comprise 1 to 4 carbon atoms, or else Ar represents an 25 aromatic heterocyclic radical having 5 ring members and comprising one or more identical or different atoms chosen from nitrogen, oxygen or sulfur atoms. More particularly, Ar represents a phenyl, 2- or 30 3-thienyl or 2- or 3-furyl radical.

- 2 More particularly still, Ar represents a phenyl radical optionally substituted by a chlorine or fluorine atom or by an alkyl (methyl), alkoxy (methoxy) or 2- or 3-thienyl or 2- or 3-furyl radical. 5 Of even more particular advantage is the product of general formula (I) in which Ar represents a phenyl radical, R 1 represents a tert-butoxycarbonyl radical and R represents an acetyl radical. 10 Mention may be made, among the processes known to date for preparing the compounds of formula (I), of patent EP 0 673 372, which discloses, starting from 10-deacetylbaccatin III, a process which consists, in a 15 first stage, in protecting the 10-deacetylbaccatin III in the 7 position, in a second stage, in acetylating in the 10 position, in a third stage, in deprotecting the 7 position, in a fourth stage, in carrying out a trifluoromethanesulfonylation (or triflation) in the 7 20 position, in a fifth stage, in carrying out a cyclopropylation in the 7-8 position, then, in a penultimate stage, in attaching the side chain in the 13 position and, finally, in a final stage, in deprotecting the side chain. The stage of 25 cyclopropylation in the 7-8 position is carried out in the presence either of an alkali metal halide (sodium iodide, potassium fluoride) or of an alkali metal azide (sodium azide) or of a quaternary ammonium salt or, finally, of an alkali metal phosphate. 30 It became apparent later, as disclosed in the patents published under the 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 35 not essential and that an additive such as as molecular sieves in the presence of sodium chloride was effective. The solvent used in these three patent applications was composed of a mixture of acetonitrile and of tetrahydrofuran.

- 3 It is also known, from the paper by Johnson, Nidy, Dobrowolski, Gebhard, Qualls, Wicnienski and Kelly which -appeared in Tetrahedron Letters, Vol. 35, No. 43, 5 pp 7893-7896, 1994, that the 7-0-triflate could be converted to 7P,8p-methanotaxane in the presence of a large excess of silica gel; the excess is 60 times the weight of the 7-0-triflate derivative, which is unusable industrially. 10 According to the present invention, the process disclosed in the three abovementioned patents has been improved by the use of sulfolane. 15 The compound of following formula (I) R-O O

R

1 NH ArO -oil OH 0 OHH HO OCOCH 3 OCOC6H5 in which Ar represents an aryl radical, 20 R represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl radical,

R

1 represents a benzoyl radical or an R 2 -0-CO radical in which R 2 represents a straight or branched alkyl radical comprising 1 to 8 carbon 25 atoms, is prepared by a process which consists in bringing the compound of formula (II) R'-O O O-SO2-CF3 \-4 (II) / H: HO OCOCH3

OCOCH

5 in which R' is a protective group for the hydroxyl functional group when R represents hydrogen in the formula (I) or one of the groups cited for R, into 5 contact with a weak base chosen from molecular sieves, then, successively or beforehand, in coupling a precursor of the side chain and, finally, in deprotecting the optionally protected hydroxyl functional groups, which comprises carrying out the 10 cyclopropanation reaction in sulfolane. The present invention also relates to a process for the preparation of an intermediate of general formula (III) R'O O HO O)COCH3 15

DCOC

6

H

5 in which R' has the same meaning as in the formula (II) above, by bringing the derivative of general formula (II) into contact with a molecular sieve, which is 20 carried out in sulfolane. In an entirely preferred way, the cyclopropylation reaction is carried out in sulfolane comprising between 2 and 5% by weight of water. The presence of water 25 makes possible the conversion of the derivative of - 5 formula (IV) below, a by-product produced during the cyclopropanation, to the derivative of formula (V); the separation of the derivative of formulae (III) and of the derivative of formula (IV) is difficult, whereas 5 the separation of the derivative of formula (V) from the derivative of formula (III) is easier. R'- 0R'- 0 HO""'1,1: H01"1-, O 0A OH HO OCOCH 3 HO OCOCH3 OCOCeH5 OCOC 6

H

5 (IV) (V) 10 For better implementation of the invention, it is preferable to operate with an amount of water of approximately 4% by weight with respect to the sulfolane. The reaction temperature is in particular between 20*C and the boiling point of the reaction 15 mixture. The addition is carried out of preferably 25 to 100% by weight of molecular sieve with respect to the substrate. As regards the reaction conditions, the 20 reaction is generally carried out between 20*C and the boiling point of the solvent for one to several hours. According to a better process for implementing the invention, use will be made of the hydrated sulfolane 25 (approximately 4% of water by weight) as reaction solvent in the presence of 100% by weight of 4 A 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 600C until the 30 substrate has been completely converted.

- 6 The product of formula (II) in which R' represents a protective group for the hydroxyl functional group or an acetyl, alkoxyacetyl or alkyl radical can be obtained by reaction of a derivative of 5 trifluoromethanesulfonic acid, such as the anhydride or the chloride, with baccatin III or 10-deacetylbaccatin III protected on its 10 position by a protective group, such as in particular trichloroethoxycarbonyl. 10 Generally, the reaction of 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 15 aliphatic amine (triethylamine) or pyridine, at a temperature of between -50 and +20*C. According to a better process for implementing the invention, where one of the preferred compounds of 20 formula (III) where R represents an acetyl group is prepared from the compound of formula (II) where R has the same meaning, after reaction of the compound of formula (II) with the molecular sieve: 25 - the crude product is isolated by a series of treatments, such as the optional addition of a solvent, such as ethyl acetate, the removal of the insoluble materials by filtration, the concentration of the reaction medium and then the crystallization by 30 addition of solvents which induce insolubility, such as those chosen in particular from water or toluene, - then either the crude product is purified by recrystallization from a solvent or solvent mixture, such as methanol, methanol as a mixture with 35 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 crude product is purified by chromatography on silica gel, elution being carried out with methylene chloride as a mixture with ethyl acetate, methanol or acetonitrile. 5 Preferably, the medium will be treated by addition of ethyl acetate, filtration of the molecular sieve, concentration under reduced pressure and precipitation by addition of water with seeding. 10 Preferably, the crude product will be purified by crystallization from an ethyl acetate/diisopropyl ether mixture with a ratio of between 50/50 v/v and 10/90 v/v and preferably equal to 25/75. 15 The product of formula (III) obtained is subsequently or previously coupled according to methods known to a person skilled in the art with a precursor of the side chain chosen from P-phenylisoserine protected in the 2' 20 position, such as disclosed in patent EP 336 840, oxazolidines, such as disclosed in particular in patents EP 595 370, EP 663 906, EP 663 907, EP 663 908, EP 666 857 and EP 669 915, or P-lactams, such as disclosed in particular in the following patents 25 EP 400 971, US 5,254,580 and US 5,466,834. The following examples illustrate the present invention but should not be regarded as a limitation on the invention. 30 EXAMPLE 1 2.0 g of 4,10 -diacetoxy-2a-benzoyloxy-5D,20-epoxy 1,13a-dihydroxy-9-oxo-7 -(trifluoromethylsulfonyloxy) 35 tax-ll-ene with a purity of 92%, 2.02 g of 4 A molecular sieve as activated powder and 1.0 g of sodium chloride are charged to 14 ml of sulfolane in a 50 ml three-necked flask and the mixture is heated at 60*C for approximately 4 hours. The reaction medium is - 8 cooled to ambient temperature and then filtered. The insoluble materials are washed in 3 times with 50 ml of ethyl acetate and the organic phases are combined. The 4,10$-diacetoxy-2a-benzoyloxy-5 ,20-epoxy-1,13a 5 dihydroxy-9-oxo-19-norcyclopropa[g]tax-11-ene (I) solution thus obtained is quantitatively determined by HPLC with respect to a standard (1.29 g, yield of 88%). Comparative examples with different solvents 10 The results are shown in the following table: Example Solvent Conditions DC Yield Observations Cl AcCN/THF 15 g, > 99% 69% 13.5% acetamido lOv/lv reflux 3 7.7% ethylen-1 hours C2 DMF 0.5 g 98% 70% 16.5% ethylen-2 40 - 50 0 C 7 hours 30 C3 NMP 0.5 g > 99% 12.6% Decomposition 50 0 C, 3 hours C4 Acetone 3 g > 99% - 5.6% ethylen-1 reflux 2 40% 7-epi OH hours OAc 0 NHCOCH, OAc 0 HO",. H" OH HO CHHO OCOCH 3 6 COCH 3 0CH brOCH, COCHs ACETAMIDO ETHYLEN-1 or (V) OAc 0 OAc 0 H HOH Ho""HO'"~ HO O OCOCH, HOOCH OCOCH, -COCH, ETHYLEN-2 or (IV) 7-epi OH -9 EXAMPLE 2 60.0 g of 4,10 -diacetoxy-2a-benzoyloxy- ,20-epoxy 1,13a-dihydroxy-9-oxo-7 -(trifluoromethylsulfonyloxy) 5 tax-ll-ene with a purity of 89.8% by weight, 60 g of 4 Angstrom molecular sieve as activated powder and 9.6 ml of water are charged to 240 g of sulfolane in a 500 ml three-necked flask and the mixture is heated with stirring at 600C for approximately 4 hours. The 10 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 the 4,10p-diacetoxy-2ax-benzoyloxy 15 5 ,20-epoxy-1,13ah-dihydroxy-9-oxo-19-norcyclopropa[g] tax-11-ene solution thus obtained is quantitatively determined by HPLC with respect to a standard (37.5 g, yield of 88%) . A fraction of the solution (152 g) is concentrated under a pressure of less than 15 mmHg at 20 45*C for approximately 45 minutes and the concentrate obtained (75.2 g) is stirred at 400C. 59.2 ml of demineralized water are added over one hour to the solution and then seeding is carried out at 40*C with 100 mg of 4,10 -diacetoxy-2a-benzoyloxy-5 ,20-epoxy 25 1,13a-dihydroxy-9-oxo-19-norcyclopropa[g]tax-11-ene. The medium is cooled to ambient temperature over 2 hours 30 minutes and then 80.3 g of demineralized water are again run in over 1 hour. The suspension is then cooled to 0-4*C over approximately 1 hour 30 minutes. 30 The product is filtered off, washed 3 times with 33 ml of demineralized water and dried under reduced pressure at 450C for 16 hours. 12.65 g of crude product are thus obtained, which product has a purity of 70.8% by weight quantitatively determined by HPLC (yield of 83%). 35 12.5 g of crude product are charged to a 100 ml round bottomed flask and are 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 4,10D-diacetoxy-2a-benzoyloxy- - 10 5$,20-epoxy-1,13a-dihydroxy-9-oxo-19-norcylcopropa[g] tax-11-ene. The suspension is then cooled to ambient temperature and then to 0-4*C over approximately 3 hours. After filtration, the product is washed twice 5 with 5 ml of diisopropyl ether and then dried under reduced pressure at 45*C for 16 hours. 7.1 g of pure product are thus obtained, which product has a purity of 97.7% by weight quantitatively determined by HPLC (recrystallization yield of 66%). 10 EXAMPLES 3 to 5 Example 2 is repeated as far as the crude product, a variable amount of water being added to the sulfolane. Example Conditions ETHYLEN-1 ETHYLEN-2 3 Sieve 600C, 4 hours 3.6 5.5 4 Sieve 600C, 4 hours, 6.9 2.4 1% water 5 Sieve 600C, 4 hours, 7.9 1.4 2% water 2 Sieve 600C, 4 hours, 8.7 0.2 4% water 15 The impurity named ETHYLEN-2 is difficult to separate from (III) by silica chromatography or crystallization; in contrast, the impurity named ETHYLEN-1 is easily removed by these same techniques. 20 EXAMPLE 6 - Purification by crystallization from methanol 58 g of 4,101 -diacetoxy-2a-benzoyloxy-P ,20-epoxy-1, 13a 25 dihydroxy-9-oxo-7 -(trifluoromethylsulfonyloxy)tax-11 ene with a purity of 92%, 58 g of 4 angstrom molecular sieve as activated powder and 29 g of sodium chloride are charged to 580 ml of ethyl acetate in a 2-liter glass reactor and the mixture is heated with stirring 30 at between 55 and 650C for approximately 46 hours. The - 11 reaction medium is cooled to ambient temperature and filtered through a bed of Clarcel 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 ,20-epoxy-1,13a-dihydroxy-9 oxo-19-norcyclopropa[g]tax-ll-ene solution thus obtained is washed with an aqueous sodium hydrogencarbonate solution (17.4 g in 290 ml of water) and then twice with 290 ml of water. The reaction 10 medium is concentrated to a volume of approximately 200 ml under reduced pressure at a temperature of less than 40*C and 825 ml of methanol are added. The change in solvent is carried out by distillation under reduced pressure at a temperature of less than 40*C with 15 addition of methanol (1145 ml in total) and then the solution is cooled to ambient temperature. Crystallization is initiated with 0.21 g of 4,10p diacetoxy-2a-benzoyloxy-5 ,20-epoxy-1,13ca-dihydroxy-9 oxo-19-norcyclopropa[g]tax-ll-ene and then the 20 suspension is cooled to 0*C over approximately 1 hour 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 product are obtained (yield of 55%), which product 25 assays at 94% by weight by HPLC quantitative determination (> 99% by area internal normalization). EXAMPLE 7 - Purification by chromatography 30 4.9 g of crude 4,10 -diacetoxy-2a-benzoyloxy-5 ,20 epoxy-1,13a-dihydroxy-9-oxo-19-norcyclopropa[g]tax-ll ene with an HPLC purity of 93.9% (internal normalization of the areas) and assaying at 65.5% by weight are purified by chromatography with 250 g of 35 silica gel, elution being carried out with a mixture of methylene chloride and ethyl acetate (v/v: 75/25) . The fractions comprising the product are combined and concentrated under reduced pressure. The solution - 12 obtained (241 g) assays at 1.3% w/w by HPLC quantative determination. The purity by HPLC is 99.4% (purification yield of 97%). 5 EXAMPLE 8 - Purification by crystallization from diisopropyl ether (DIPE) 23 g of crude 4,10p-diacetoxy-2at-benzoyloxy-5p,20 epoxy-1,13x-dihydroxy-9-oxo-19-norcylcopropa[g]tax-li 10 ene with a purity of 91% by HPLC and assaying at 77.5% by weight are dissolved in approximately 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 approximately 15 300C to a residual volume of approximately 74 ml. 222 ml of diisopropyl ether are then added to the solution over 4 to 7 hours at ambient temperature and then the suspension obtained is cooled to 20C. The suspension is cooled and the product cake is washed 20 with 36 ml of diisopropyl ether. After drying under reduced pressure at 25 0 C, 17.6 g of purified 4,10 diacetoxy-2a-benzoyloxy-5D,20-epoxy-1,13x-dihydroxy-9 oxo-19-norcyclopropa[g]tax-li-ene are obtained, which product has a purity of approximately 97% and assays at 25 89.3% by weight (yield of 88%). Example 8 is repeated with different recrystallization solvents. Example Conditions RY% ETHYLEN-1 ETHYLEN-2 8 AcOEt/DIPE 88 0.3 27/75 9 MeOH/DIPE 82 1.7 0.2 70/30 10 MeOH/toluene 47 0.3 0.2 50/50 11 AcOEt/DIPE 88 0.2 50/50

Claims (13)

1. A process for the preparation of the compound of formula (I) R-O O R,-NH 0 A - OI Ar OH :0 H HO iOCOCH3 OCOC6H5 in which Ar represents an aryl radical, R represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl radical, R, represents a benzoyl radical or an R 2 -0-CO radical in which R 2 represents a straight or branched alkyl radical comprising 1 to 8 carbon atoms, by a process which consists in bringing the compound of formula (II) R'-O 0 O-SO2-CF3 (II) HOH HO i OCOCH, HO 3 OCOC H5 in which R' is a protective group for the hydroxyl functional group when R represents hydrogen in the - 14 formula (I) or one of the groups cited for R, into contact with a weak base chosen from molecular sieves, then, successively or beforehand, in coupling a precursor of the side chain and, finally, in deprotecting the optionally protected hydroxyl functional groups, which comprises carrying out the cyclopropanation reaction in sulfolane.

2. The process as claimed in claim 1, wherein R is an acetyl radical, R 1 is a tert-butoxycarbonyl radical and Ar is a phenyl radical.

3. The process as claimed in claim 1, wherein the reaction is carried out in the presence of 4 A molecular sieve as activated powder.

4. The process as claimed in claims 1 and 3, wherein use is made of a ratio by weight of the molecular sieve to the compound of formula (II) of approximately 100% by weight.

5. The process as claimed in claims 1 to 4, wherein the sulfolane comprises 2 to 5% by weight of water.

6. The process as claimed in claim 5, wherein the sulfolane comprises approximately 4% of water.

7. The process as claimed in claim 1 to 6, wherein the reaction temperature is between 20 0 C and the boiling point of the solvent.

8. The process as claimed in claim 6, wherein the reaction temperature is approximately 600C.

9. The process as claimed in claim 1, wherein the crude product is isolated by addition of ethyl acetate to the reaction medium, filtration of the - 15 molecular sieve, concentration of the reaction medium and then crystallization by addition of water.

10. The process as claimed in claim 9, wherein, after isolation, the crude product is purified by recrystallization from a solvent or solvent mixture chosen 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. The process as claimed in claim 10, wherein the crude product is purified with a mixture of ethyl acetate and isopropyl ether according to a ratio of approximately 25/75 v/v.

12. The process as claimed in claim 1, wherein the precursor of the side chain is chosen by derivatives of p-phenylisoserine protected in the 2' position, oxazolidines or P-lactams.

13. A process for the preparation of an intermediate of general formula (III) R'O 0 HO - OCOCH3 DOCOC6H5 in which R' has the same meaning as in the formula (II) of claim 1, - 16 by bringing a derivative of general formula (II) R'-0 0 0-SO2-CF3 (II) HOI"' HO zOCOCH3 OCOC 6 H 5 into contact with a molecular sieve, which is carried out in sulfolane.