Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-05-05
2000-10-03
Trinh, Ba K.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
549511, C07D30514
Patent
active
061275557
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for the monoacylation of hydroxytaxanes. The invention relates more particularly to a process for the selective monoacylation of 10-deacetylbaccatin III or derivatives thereof.
10-Deacetylbaccatin III (10-DAB), represented by the general formula (I) in which R.sub.1 represents a hydrogen atom, and baccatin III, represented by the general formula (I) in which R.sub.1 represents an acetyl radical, may be extracted from yew leaves and constitute advantageous starting materials in the semi-synthesis of paclitaxel (Taxol.RTM.), docetaxel (Taxotere.RTM.) and derivatives thereof. ##STR1##
However, 10-DAB is more readily accessible and is extracted from the leaves in larger amounts than baccatin III.
It is known from the work of F. Gueritte-Voegelein et al., Tetrahedron, 42, 4451-4460 (1986) that the acetylation of 10-DAB with acetic anhydride is unselective. When the reaction takes place under mild operating conditions (24 hours at 20.degree. C.) an equimolar mixture of 7-monoacetyl and 7,10-diacetyl derivatives is formed. More vigorous conditions (48 hours at 60.degree. C.) lead to the formation of 7,10-diacetyl and 7,10,13-triacetyl derivatives in equal amounts. At an even higher temperature (24 hours at 80.degree. C.), the 7,10,13-triacetyl derivative is exclusively formed.
It is also known from J- N. Denis and A. E. Greene, J. Am. Chem. Soc. 110, 5917-5919 (1988) that 10-DAB can be acetylated in position 10 with acetyl chloride on condition that the hydroxyl in position 7 is selectively protected beforehand with a triethylsilyl group.
PCT application WO 95/26961 describes the preparation of baccatin III from 10-DAB in three steps: protection of the hydroxyl in position 7 by the action of a trialkylsilyl halide, acetylation of the hydroxyl in position 10 with acetic anhydride and, lastly, deprotection of the trialkylsilyl group in position 7 using trifluoroacetic acid.
Taking these results into account, it follows that any reaction allowing differentiation between the free hydroxyls in positions 7 and 10 of 10-DAB or derivatives thereof, in particular selective acylation, is of great importance in the synthesis of taxoids.
The present invention describes, for the first time, a selective monoacylation reaction of the hydroxyl in position C-10 of 10-deacetylbaccatin III or derivatives thereof in position C-2 and/or in position C-4.
It is known from W. Kantlehner, Adv. Org. Chem., vol. 9, part 2, 65-141 and 181-277 (1976) that halo-methyleneiminiums can react with alcohols to give intermediate alkoxymethyleneiminium halides which lead, after hydrolysis, to the corresponding esters with elimination of an alkylamine.
It has now been found that 10-deacetylbaccatin III or derivatives thereof in position C-2 and/or in position C-4 can be selectively monoacylated in position 10 using a methyleneiminium salt corresponding to the general formula (II): ##STR2## in which R.sub.2 represents: a hydrogen atom, atoms, atoms, alkylthiocarbonyl group in which the alkyl part contains 1 to 12 carbon atoms, or one or more hetero atoms chosen from sulfur, oxygen and nitrogen, chosen from: and one or more hetero atoms chosen from sulfur, oxygen and nitrogen, or alternatively and the methylenic carbon, a 4- to 7-membered ring, such as 2-piperidone, 2-azetidinone, 2-pyrrolidinone or caprolactam, atoms, atoms, substituted, saturated or unsaturated 4- to 6-membered heterocycle, halosulfinyloxy, halosulfonyloxy, alkylsulfonyloxy, arylsulfonyloxy, alkylaminosulfonyloxy, alkylcarbonyloxy, arylcarbonyloxy, halophosphinyloxy, halophosphoranyloxy, haloalkylsulfonyloxy or haloalkylcarbonate group, arylsulfonates, alkylaminosulfonates, alkylcarboxylates, arylcarboxylates and phosphorodihalidates, or [M(Z).sub.n ].sup.- in which 4.ltoreq.n.ltoreq.6, Z is a halogen atom and M is an element from the Periodic Table which can have an oxidation state equal to or greater than 3 and preferably between 3 and 5.
More particularly, (Hal)SO.sub.2 --O--, R.sub.a SO.sub.2 --O--or R.sub.a CO.sub.2 in which R.sub.a rep
REFERENCES:
F. Gueritte-Voegelein et al., Chemical Studies of 10-Deacetyl Baccatin III. Hemisynthesis of Taxol Derivatives, Tetrahedron, vol. 42, pp. 4451-4460 (1986).
J.-N. Denis et al., A Highly Efficient, Practical Approach to Natural Taxol, J. Am. Chem. Soc., vol. 110, pp. 5917-5919 (1988).
H.S. Mosher et al., The Reaction of P.sub.2 I.sub.4 and N,N-Dimethylformamide, Synthetic Communications, vol. 11, pp. 733-736 (1981).
P.L. Fuchs et al., Conversion of Amides and Lactams to Thioamides and Thiolactams Using Hexamethyldisilathiane, J. Org. Chem., vol. 59, pp. 348-354 (1994).
A. Martinez et al., A New Procedure for Formylation of Less Active Aromatics, J. Chem. Soc., Chem. Commun., pp. 1571-1572 (1990).
H. Heaney et al., Vilsmeier Formylation and Glyoxylation Reactions of Nucleophilic Aromatic Compounds Using Pyrophosphoryl Chloride, Tetrahedron, vol. 49, pp. 4015-4034 (1993).
Didier Eric
Pecquet Pascal
Aventis Pharma S.A.
Trinh Ba K.
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