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EP0598793A1 - METHOD FOR PREPARING 13$g(a)-CINNAMOYL BACCATINE III OR 10-DEACETYL BACCATINE III - Google Patents

METHOD FOR PREPARING 13$g(a)-CINNAMOYL BACCATINE III OR 10-DEACETYL BACCATINE III

Info

Publication number
EP0598793A1
EP0598793A1 EP92917152A EP92917152A EP0598793A1 EP 0598793 A1 EP0598793 A1 EP 0598793A1 EP 92917152 A EP92917152 A EP 92917152A EP 92917152 A EP92917152 A EP 92917152A EP 0598793 A1 EP0598793 A1 EP 0598793A1
Authority
EP
European Patent Office
Prior art keywords
general formula
deacetyl
iii
baccatin iii
baccatin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP92917152A
Other languages
German (de)
French (fr)
Inventor
Sophie De Suzzoni
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharma SA
Original Assignee
Rhone Poulenc Rorer SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rhone Poulenc Rorer SA filed Critical Rhone Poulenc Rorer SA
Publication of EP0598793A1 publication Critical patent/EP0598793A1/en
Ceased legal-status Critical Current

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D305/00Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to a new process for the preparation of cinnamoyl-13 ⁇ baccatin III or deacetyl-10 baccatin III of general formula:
  • OCOCgH 5 in which Rj represents an acetyl or 2,2,2-trichloroethoxycarbonyl radical.
  • OCOC 6 H 5 by operating in an aromatic hydrocarbon in the presence of a condensing agent such as a carbodiimide (dicyclohexylcarbodiimide) or a reactive carbonate (dipyridyl-2 carbonate) and an activating agent such as dimethylaminopyridine at a temperature between 6 and 90 ° C.
  • a condensing agent such as a carbodiimide (dicyclohexylcarbodiimide) or a reactive carbonate (dipyridyl-2 carbonate)
  • an activating agent such as dimethylaminopyridine
  • the product of general formula (I) can be obtained by the action of a mixed anhydride of cinnamic acid with a substituted benzoic acid on the derivative of baccatin III or 10-deacetyl baccatin III in basic medium using a mole of mixed anhydride per mole of baccatin III derivative or of 10-deacetyl baccatin m.
  • R represents 1 to 5 substituents, identical or different, chosen from halogen atoms (chlorine, bromine) and nitro, methyl or methoxy radicals, can be obtained by the action of cinnamic acid on the acid chloride of a benzoic acid of general formula:
  • the mixed anhydride of general formula (III) is obtained by the action of the acid chloride of general formula (IV) on cinnamic acid in solution in a suitable organic solvent such as tetrahydrofuran in the presence of a organic base such as a tertiary amine such as triethylamine at a temperature between 0 and 30 ° C.
  • a suitable organic solvent such as tetrahydrofuran
  • a organic base such as a tertiary amine such as triethylamine
  • the reaction of the mixed anhydride of general formula (III) with the derivative of baccatin III or of desacetyl-10 baccatin III is carried out by slowly adding a solution mixed anhydride in an organic solvent suitable for a solution of the derivative of baccatin m or deacetyl-10 baccatin III in the same solvent in the presence of a condensing agent such as pyrrolidinopyridine or dimethylaminopyridine. It is particularly advantageous to operate under an inert atmosphere such as an argon atmosphere.
  • an aromatic hydrocarbon is preferably used, chosen from benzene, toluene or xylenes, or an ether such as tetrahydrofuran.
  • R represents a butoxy or phenyl radical and R'j represents a hydrogen atom or an acetyl radical according to the methods described in European patent applications EP-A-0253 738 and EP-A-0253 739.
  • the toluene phase is washed with N hydrochloric acid, with sodium hydrogen carbonate in 2.5% aqueous solution and is then dried over sodium sulfate. After filtration and concentration to dryness under reduced pressure, the residue obtained is purified by chromatography on silica (0.015-0.025 mm), eluting with a toluene-ether mixture (95-5 by volume). 2.5 g of cinnamoyl-13 ⁇ bis- [(2,2,2-trichloroethoxy) carbonyloxy] -7 ⁇ , 10 ⁇ deacetyl-10 baccatin III, the characteristics of which are identical to, are obtained with a yield of 61.9%. those described by F. GUERITTE-VOEGELEIN et al., Tetrahedron, Vol. 42, No. 16, 4451-4460 (1986).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epoxy Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Procédé de préparation de la cinnamoyl-13alpha baccatine III ou désacétyl-10 baccatine III de formule (I) par condensation d'un anhydride mixte de formule générale (II) sur un dérivé de la baccatine III ou de la désacétyl-10 baccatine III de formule générale (III). Dans les formules (I) et (III), R1 représente un radical acétyle ou trichloro-2,2,2 éthoxycarbonyle. Dans la formule (II), R représente 1 à 5 substituants, identiques ou différents (halogène, nitro, méthyle, méthoxy).Process for the preparation of cinnamoyl-13alpha baccatin III or 10-deacetyl baccatin III of formula (I) by condensation of a mixed anhydride of general formula (II) on a derivative of baccatin III or of 10-deacetyl baccatin III of general formula (III). In formulas (I) and (III), R1 represents an acetyl or 2,2,2-trichloroethoxycarbonyl radical. In formula (II), R represents 1 to 5 substituents, identical or different (halogen, nitro, methyl, methoxy).

Description

PROCEDE DE PREPARATION DE LA CINNAMOYL-13« PROCESS FOR THE PREPARATION OF CINNAMOYL-13 "

BACCATINE IΠ OU DESACETYL-IQ BACCATINE mBACCATINE IΠ OR DESACETYL-IQ BACCATINE m

La présente invention concerne un nouveau procédé de préparation de la cinnamoyl-13α baccatine III ou désacétyl-10 baccatine III de formule générale :The present invention relates to a new process for the preparation of cinnamoyl-13α baccatin III or deacetyl-10 baccatin III of general formula:

ÔCOCgH5 dans laquelle Rj représente un radical acétyle ou trichloro-2,2,2 éthoxycarbonyle. OCOCgH 5 in which Rj represents an acetyl or 2,2,2-trichloroethoxycarbonyl radical.

Dans le brevet européen EP-0253 738 a été décrite la préparation du produit de formule générale (I) par action de l'acide cinnamique sur un dérivé de la baccatine m ou de la désacétyl-10 baccatine III de formule générale :In European patent EP-0253 738, the preparation of the product of general formula (I) was described by the action of cinnamic acid on a derivative of baccatin m or of 10-deacetyl baccatin III of general formula:

OCOC6H5 en opérant dans un hydrocarbure aromatique en présence d'un agent de condensation tel qu'un carbodiimide (dicyclohexylcarbodiimide) ou un carbonate réactif (dipyridyl-2 carbonate) et d'un agent d'activation tel que la diméthylaminopyridine à une température comprise entre 6 et 90°C. Pour la mise en oeuvre du procédé il est nécessaire d'utiliser au moins 4 moles d'acide cinnamique par mole de baccatine III ou de désacétyl-10 baccatine III de formule générale (II) pour obtenir des résultats satisfaisants.OCOC 6 H 5 by operating in an aromatic hydrocarbon in the presence of a condensing agent such as a carbodiimide (dicyclohexylcarbodiimide) or a reactive carbonate (dipyridyl-2 carbonate) and an activating agent such as dimethylaminopyridine at a temperature between 6 and 90 ° C. For the implementation of the process it is necessary to use at least 4 moles of cinnamic acid per mole of baccatin III or of 10-deacetyl baccatin III of general formula (II) to obtain satisfactory results.

Il a maintenant été trouvé, et c'est ce qui fait l'objet de la présente invention que le produit de formule générale (I) peut être obtenu par action d'un anhydride mixte de l'acide cinnamique avec un acide benzoïque substitué sur le dérivé de la baccatine III ou de la désacétyl-10 baccatine III en milieu basique en utilisant une mole d'anhydride mixte par mole de dérivé de la baccatine III ou de la désacétyl-10 baccatine m.It has now been found, and this is what is the subject of the present invention, that the product of general formula (I) can be obtained by the action of a mixed anhydride of cinnamic acid with a substituted benzoic acid on the derivative of baccatin III or 10-deacetyl baccatin III in basic medium using a mole of mixed anhydride per mole of baccatin III derivative or of 10-deacetyl baccatin m.

L'anhydride mixte de formule générale :The mixed anhydride of general formula:

dans laquelle R représente 1 à 5 substituants, identiques ou différents, choisis parmi les atomes d'halogène (chlore, brome) et les radicaux nitro, méthyle ou méthoxy, peut être obtenu par action de l'acide cinnamique sur le chlorure d'acide d'un acide ben¬ zoïque de formule générale : in which R represents 1 to 5 substituents, identical or different, chosen from halogen atoms (chlorine, bromine) and nitro, methyl or methoxy radicals, can be obtained by the action of cinnamic acid on the acid chloride of a benzoic acid of general formula:

dans laquelle R est défini comme précédemment dans les conditions décrites par J. INANAGA et al., Bull. Chem. Soc. Japan, 52 (7) 1989-1993 (1979). D'un intérêt tout particulier est le chlorure de l'acide trichloro-2,4,6 benzoïque. in which R is defined as above under the conditions described by J. INANAGA et al., Bull. Chem. Soc. Japan, 52 (7) 1989-1993 (1979). Of particular interest is the chloride of 2,4,4,6-trichloro benzoic acid.

Généralement, l'anhydride mixte de formule générale (III) est obtenu par action du chlorure d'acide de formule générale (IV) sur l'acide cinnamique en solu- tion dans un solvant organique convenable tel que le tétrahydrofuranne en présence d'une base organique telle qu'une aminé tertiaire comme la triéthylamine à une tem¬ pérature comprise entre 0 et 30°C.Generally, the mixed anhydride of general formula (III) is obtained by the action of the acid chloride of general formula (IV) on cinnamic acid in solution in a suitable organic solvent such as tetrahydrofuran in the presence of a organic base such as a tertiary amine such as triethylamine at a temperature between 0 and 30 ° C.

De préférence, afin d'éviter les réactions secondaires, la réaction de l'anhy¬ dride mixte de formule générale (III) sur le dérivé de la baccatine III ou de la désacé- tyl-10 baccatine III est effectuée en ajoutant lentement une solution de l'anhydride mixte dans un solvant organique convenable à une solution du dérivé de la baccatine m ou de la désacétyl-10 baccatine III dans le même solvant en présence d'un agent de condensation tel que la pyrrolidinopyridine ou la diméthylaminopyridine. Il est parti¬ culièrement avantageux d'opérer sous une atmosphère inerte telle qu'une atmosphère d'argon.Preferably, in order to avoid side reactions, the reaction of the mixed anhydride of general formula (III) with the derivative of baccatin III or of desacetyl-10 baccatin III is carried out by slowly adding a solution mixed anhydride in an organic solvent suitable for a solution of the derivative of baccatin m or deacetyl-10 baccatin III in the same solvent in the presence of a condensing agent such as pyrrolidinopyridine or dimethylaminopyridine. It is particularly advantageous to operate under an inert atmosphere such as an argon atmosphere.

Comme solvant, on utilise de préférence un hydrocarbure aromatique, choisi parmi le benzène, le toluène ou les xylènes, ou un éther tel que le tétrahydrofuranne.As solvent, an aromatic hydrocarbon is preferably used, chosen from benzene, toluene or xylenes, or an ether such as tetrahydrofuran.

Il est particulièrement avantageux d'opérer à une température comprise entre 40 et 110°C et de préférence à 80°C. Le produit de formule générale (I) obtenu par le procédé selon la présente invention peut être transformé en produit de formule générale :It is particularly advantageous to operate at a temperature between 40 and 110 ° C and preferably at 80 ° C. The product of general formula (I) obtained by the process according to the present invention can be transformed into product of general formula:

C6H5 dans laquelle R représente un radical butoxy ou phényle et R'j représente un atome d'hydrogène ou un radical acétyle selon les procédés décrits dans les demandes de brevet européen EP-A-0253 738 et EP-A-0253 739.C 6 H 5 in which R represents a butoxy or phenyl radical and R'j represents a hydrogen atom or an acetyl radical according to the methods described in European patent applications EP-A-0253 738 and EP-A-0253 739.

L'exemple suivant illustre la présente invention.The following example illustrates the present invention.

EXEMELEEXAMPLE

A 0,605 g d'acide cinnamique (4 mmoles) en solution dans 10 cm3 de tétra- hydrofuranne anhydre, on ajoute 0,580 ml de triéthylamine anhydre. On ajoute alors, sous atmosphère d'azote, 0,640 ml de chlorure de trichloro-2,4,6 benzoyle (4,1 mmoles) dans 10 cm3 de tétrahydrofuranne anhydre. On agite pendant 1 heure à une température voisine de 20°C. Le chlorhydrate de triéthylamine est séparé par filtra¬ tion sur verre fritte. Le tétrahydrofuranne est éliminé sous pression réduite. L'anhy- dride mixte ainsi obtenu est repris par 50 cm3 de toluène anhydre.To 0.605 g of cinnamic acid (4 mmol) dissolved in 10 cm3 of anhydrous tetrahydrofuran, 0.580 ml of anhydrous triethylamine is added. 0.640 ml of 2,4,6-benzoyl trichloro chloride (4.1 mmol) in 10 cm 3 of anhydrous tetrahydrofuran is then added under a nitrogen atmosphere. The mixture is stirred for 1 hour at a temperature in the region of 20 ° C. The triethylamine hydrochloride is separated by filtration on sintered glass. The tetrahydrofuran is removed under reduced pressure. The mixed anhydride thus obtained is taken up in 50 cm3 of anhydrous toluene.

Dans un tricol, on dissout, sous atmosphère d'argon, 4,02 g de bis- [(trichloro-2,2,2 éthoxy) carbonyloxy]-7β,10β désacétyl-10 baccatine III (4,48 mmoles) et 1,16 g de pyrrolidinopyridine (7,83 mmoles) dans 50 cm3 de toluène anhydre en chauffant à 80°C. On ajoute alors, goutte à goutte, l'anhydride mixte au moyen d'une ampoule à égalisation de pression. L'évolution de la réaction est suivie par chromatographie en couche mince. Après 3 heures à 80βC, il se forme 70 % d'ester.In a three-necked flask, 4.02 g of bis- [(2,2,2-trichloroethoxy) carbonyloxy] -7β, 10β deacetyl-10 baccatin III (4.48 mmol) and 1 are dissolved, under an argon atmosphere. , 16 g of pyrrolidinopyridine (7.83 mmol) in 50 cm3 of anhydrous toluene while heating to 80 ° C. The mixed anhydride is then added dropwise using a pressure equalization bulb. The progress of the reaction is followed by thin layer chromatography. After 3 hours at 80 β C, 70% of ester is formed.

La phase toluénique est lavée par de l'acide chlorhydrique N, par de l'hydro- génocarbonate de sodium en solution aqueuse à 2,5 % puis est séchée sur sulfate de sodium. Après filtration et concentration à sec sous pression réduite, le résidu obtenu est purifié par chromatographie sur silice (0,015-0,025 mm) en éluant par un mélange toluène-éther (95-5 en volumes). On obtient, avec un rendement de 61,9 %, 2,5 g de cinnamoyl-13α bis- [(trichloro-2,2,2 éthoxy) carbonyloxy]-7β,10β désacétyl-10 baccatine III dont les caractéristiques sont identiques à celles qui sont décrites par F. GUERITTE- VOEGELEIN et coll., Tetrahedron, Vol. 42, N° 16, 4451-4460 (1986). The toluene phase is washed with N hydrochloric acid, with sodium hydrogen carbonate in 2.5% aqueous solution and is then dried over sodium sulfate. After filtration and concentration to dryness under reduced pressure, the residue obtained is purified by chromatography on silica (0.015-0.025 mm), eluting with a toluene-ether mixture (95-5 by volume). 2.5 g of cinnamoyl-13α bis- [(2,2,2-trichloroethoxy) carbonyloxy] -7β, 10β deacetyl-10 baccatin III, the characteristics of which are identical to, are obtained with a yield of 61.9%. those described by F. GUERITTE-VOEGELEIN et al., Tetrahedron, Vol. 42, No. 16, 4451-4460 (1986).

Claims

REVENDICATIONS 1 - Procédé de préparation d'un dérivé du taxane de formule générale1 - Process for the preparation of a taxane derivative of general formula dans laquelle R\ représente un radical acétyle ou un radical trichloro-2,2,2 éthoxy- carbonyle caractérisé en ce que l'on fait réagir un anhydride mixte de formule générale in which R \ represents an acetyl radical or a 2,2,2-trichloroethoxycarbonyl radical characterized in that a mixed anhydride of general formula is reacted dans laquelle R représente 1 à 5 substituants choisis parmi les atomes d'halogène et les radicaux nitro, méthyle ou méthoxy, sur un dérivé de la baccatine III ou désacé- tyl-10 baccatine m de formule générale : in which R represents 1 to 5 substituents chosen from halogen atoms and nitro, methyl or methoxy radicals, on a baccatin III or desacetyl-10 baccatin m derivative of general formula: dans laquelle Rj représente un radical acétyle ou trichloro-2,2,2 éthoxycarbonyle. in which Rj represents an acetyl or 2,2,2-trichloroethoxycarbonyl radical. 2 - Procédé selon la revendication 1 caractérisé en ce que l'on opère dans un solvant organique choisi parmi les hydrocarbures aromatiques et les éthers.2 - Process according to claim 1 characterized in that one operates in an organic solvent chosen from aromatic hydrocarbons and ethers. 3 - Procédé selon l'une des revendications 1 ou 2 caractérisé en ce que l'on opère en présence d'une base organique. 4 - Procédé selon la revendication 3 caractérisé en ce que la base est choisie parmi la pyrrolidinopyridine ou la diméthylaminopyridine.3 - Method according to one of claims 1 or 2 characterized in that one operates in the presence of an organic base. 4 - Process according to claim 3 characterized in that the base is chosen from pyrrolidinopyridine or dimethylaminopyridine. 5 - Procédé .selon l'une des revendications 1 à 4 caractérirè en ce que l'on utilise une mole d'anhydride mixte par mole de dérivé de la baccatine III ou de la désacétyl-10 baccatine IH.5 - Method. According to one of claims 1 to 4 characterized in that one uses a mole of mixed anhydride per mole of derivative of baccatin III or 10-deacetyl baccatin IH. 6 - Procédé selon l'une des revendications 1 à 5 caractérisé en ce que l'on opère à une température comprise entre 40 et 110°C. 6 - Method according to one of claims 1 to 5 characterized in that one operates at a temperature between 40 and 110 ° C.
EP92917152A 1991-07-25 1992-07-23 METHOD FOR PREPARING 13$g(a)-CINNAMOYL BACCATINE III OR 10-DEACETYL BACCATINE III Ceased EP0598793A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9109424A FR2679558B1 (en) 1991-07-25 1991-07-25 PROCESS FOR THE PREPARATION OF CINNAMOYL-13ALPHA BACCATIN III OR DESACETYL-10 BACCATIN III.
FR9109424 1991-07-25
PCT/FR1992/000725 WO1993002066A1 (en) 1991-07-25 1992-07-23 METHOD FOR PREPARING 13α-CINNAMOYL BACCATINE III OR 10-DEACETYL BACCATINE III

Publications (1)

Publication Number Publication Date
EP0598793A1 true EP0598793A1 (en) 1994-06-01

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Family Applications (2)

Application Number Title Priority Date Filing Date
EP92402123A Pending EP0526311A1 (en) 1991-07-25 1992-07-23 Process for the preparation of 13alpha-cinnamoylbaccatine III or 10-deacetylbaccatine III
EP92917152A Ceased EP0598793A1 (en) 1991-07-25 1992-07-23 METHOD FOR PREPARING 13$g(a)-CINNAMOYL BACCATINE III OR 10-DEACETYL BACCATINE III

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP92402123A Pending EP0526311A1 (en) 1991-07-25 1992-07-23 Process for the preparation of 13alpha-cinnamoylbaccatine III or 10-deacetylbaccatine III

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EP (2) EP0526311A1 (en)
JP (1) JPH06508851A (en)
AU (1) AU2416892A (en)
CA (1) CA2113444A1 (en)
CZ (1) CZ14894A3 (en)
FI (1) FI940338A7 (en)
FR (1) FR2679558B1 (en)
HU (1) HUT66773A (en)
IE (1) IE922433A1 (en)
MX (1) MX9204323A (en)
NO (1) NO940247D0 (en)
NZ (1) NZ243690A (en)
SK (1) SK8094A3 (en)
WO (1) WO1993002066A1 (en)
YU (1) YU72892A (en)
ZA (1) ZA925560B (en)

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CN1301139C (en) * 1995-08-29 2007-02-21 菲迪亚高级生物聚合物公司 Biomaterials for preventing post-surgical adhesions comprised of hyaluronic acid derivs.
AU2002301803B2 (en) 2001-11-08 2004-09-09 L'oreal Cosmetic compositions containing an aminosilicone and a conditioner, and uses thereof
FR2831805B1 (en) 2001-11-08 2004-08-06 Oreal PROCESS FOR PERMANENT DEFORMATION OF HAIR USING PARTICULAR AMINO SILICONES
FR2831803B1 (en) 2001-11-08 2004-07-30 Oreal COSMETIC COMPOSITIONS CONTAINING AN AMINO SILICONE AND A THICKENING AGENT AND THEIR USES

Family Cites Families (1)

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Publication number Priority date Publication date Assignee Title
FR2601676B1 (en) * 1986-07-17 1988-09-23 Rhone Poulenc Sante PROCESS FOR THE PREPARATION OF TAXOL AND DESACETYL-10 TAXOL

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9302066A1 *

Also Published As

Publication number Publication date
FI940338L (en) 1994-01-24
FR2679558B1 (en) 1993-09-24
NO940247L (en) 1994-01-24
HUT66773A (en) 1994-12-28
IE922433A1 (en) 1993-01-27
EP0526311A1 (en) 1993-02-03
FI940338A0 (en) 1994-01-24
AU2416892A (en) 1993-02-23
MX9204323A (en) 1993-05-01
SK8094A3 (en) 1994-06-08
ZA925560B (en) 1993-04-28
FR2679558A1 (en) 1993-01-29
CZ14894A3 (en) 1994-06-15
NZ243690A (en) 1994-06-27
HU9400200D0 (en) 1994-05-30
YU72892A (en) 1995-03-27
FI940338A7 (en) 1994-01-24
CA2113444A1 (en) 1993-02-04
NO940247D0 (en) 1994-01-24
JPH06508851A (en) 1994-10-06
WO1993002066A1 (en) 1993-02-04

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