Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-05-19
2001-01-30
Aulakh, Charanjit S. (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S511000
Reexamination Certificate
active
06180802
ABSTRACT:
This application is a 371 of PCT/FR96/02097 filed Dec. 27, 1996 now WO 97/24345 Jul. 10, 1997.
The present invention relates to new intermediates for the semisynthesis of taxanes and to the processes for preparing them.
Taxanes, natural substances whose diterpenic backbone is generally esterified with a &bgr;-amino acid side chain derived from N-alkyl- or N-aroyl-phenyl-isoserine, are known as anticancer agents. There are several tens of taxanes isolated from Taxaceae of the genus Taxus, such as for example, PACLITAXEL (R1=Ac, R2=Ph, R3=R4=H), cephalomanin, their derivatives which are deacetylated at the 10-position, or baccatins (derivatives without a side chain) represented by the formulae 1 and 2 below.
1
2
R
10
R
3′
R
7
R
2′
PACLITAXEL (e.g. TAXOL) 1a
Ac
Ph
H
H
10-DEACETYL-TAXOL 1b
H
Ph
H
H
CEPHALOMANNIN 1c
Ac
tBu
H
H
10-DEACETYL-CEPHALOMANNIN 1d
H
tBu
H
H
DOCETAXEL (e.g. TAXOTERE) 1e
H
TBO
H
H
BACCATIN (TETRAOL) 2a
Ac
—
H
H
10-DEACETYL-BACCATIN 2b
H
—
H
H
Baccatin part protected 2
G
—
G
—
In an effort not to rapidly exhaust its original source, T. brevifolia, French researchers have sought to isolate PACLITAXEL from renewable parts (the leaves) of the European yew tree. They have thus identified the probable biogenetic precursor of taxanes, 10-deacetylbaccatin III, an ideal springboard for semisynthesis, because of its relative abundance in the leaf extracts.
The semisynthesis of taxanes, such as PACLITAXEL or DOCETAXEL (R1=AC, R2=t.butyloxy, R3=R4=H), therefore consists in esterifying the hydroxyl at the 13-position of a protected derivative of baccatin or of 10-deacetylbaccatin III with a &bgr;-amino acid derivative.
Various processes for the semisynthesis of PACLITAXEL or of DOCETAXEL are described in the state of the art EP-0,253,738, EP-0,336,840, EP-0,336,841, EP-0,495,718, WO 92/09589, WO 94/07877, WO 94/07878, WO 94/07879, WO 94/10169, WO 94/12482, EP-0,400,971, EP-0,428,376, WO 94/14787. Two recent manuals I. Georg, T. T. Chen, I Ojima, and D. M. Vyas, “Taxane Anticancer Agents, Basic Science and Current Status”, ACS Symposium Series 583, Washington (1995) and in particular Matthew Suffness, “TAXOL® Science and Applications” CRC press, and 1500 cited references comprise exhaustive compilations of the semisyntheses of taxanes.
The selective monoprotection of taxanes dihydroxylated at the 7- and 10-positions has so far been obtained only with the aid of trialkylsilane ether groups (EP-A-0,336,840). This protection is of great interest because, on the one hand, of the rarity, for example, of baccatin III, direct precursor of PACLITAXEL and, on the other hand, of the impossibility of manufacturing it under profitable conditions from its much more easily available homologue, 10-deacetylbaccatin III, without an effective selective protection at the 10-position.
Indeed, the use of common groups such as acetate groups, or even of slightly hindered haloalkoxycarbonyls such as the conventional trichloroethoxycarbonyl to protect dihydroxytaxanes such as 10-deacetylbaccatin III, has the disadvantage of not at all being selective. On the other hand, they have up until now been widely used in the nonselective deprotection of 7,10-dihydroxytaxanes such as 10-deacetylbaccatin III, to give 7,10-di-(2,2,2-trichloroethoxycarbonyloxy)-10-deacetylbaccatin III, a key intermediate in the synthesis of DOCETAXEL (EP-A-0,336,841).
The use of trialkylsilanes for the protection of the hydroxyl situated at the 7-position of taxanes which are dihydroxylated at: the 7- and 10-positions has, because of the relative lability of these protecting groups towards slightly acidic media, a number of major disadvantages which counterbalance their good selectivity. The disadvantages are
1/ Subsequent acylation at the 10-position, which justifies prior selective protection at the 7-position, which is the case in the present invention, gives rise to 50 to 60% average yields because of the ease of trialkylsilylated ethers to be substituted by the acylating group present in the reaction medium, this situation being worsened by the greater difficulty of esterifying the 10-position when the 7-position is already occupied by a bulky group. This side reaction can be avoided provided it is carried out at a very low temperature using an alkali metal alcoholate as intermediate, but would introduce a new double disadvantage for an industrial synthesis as indicated in application WO-A-94/14787.
2/ The sensitivity of the alkylsilylated ethers to acidic conditions limits the possibilities of using acidic reagents in treatments of the subsequent synthetic sequence and therefore makes the field of application of these protecting groups a lot narrower. Furthermore, it should be noted that higher homologues such as tert-butyldimethylsilyl ether are thought to be more resistant to these conditions, but their introduction is made impossible because of their excessively large steric hindrance.
3/ The well-known sensitivity of alkylsilylated ethers to hydroxylated solvents such as water and alcohols makes the use of these solvents impossible in recrystallizations, systems which are nevertheless valuable because they are highly purifying in this series of compounds, which is another major disadvantage.
4/ The partial decomposition, during industrial chromatographic purifications of intermediates carrying silylated ethers, practically does not allow this purification technique to be used even though it is valuable for the purpose of producing high value-added pharmaceutical raw materials of high purity.
The taxoids not carrying a side chain of the following formula 3a:
in which
R
1
, R
2
, R
4
, R
5
, R
6
, R
14
represent, independently of each other, a radical Q, with:
Q=R, H, OH, OR, SH, SR, OCOR, OCOOR, HCO, or X, and
X=halogen, and
R represents, a linear or branched alkyl, alkenyl, of alkynyl, alkenyl, or a alkynyl radical, a perhaloalkyl radical, a, heteroalkenyl, or heteroalkynyl linear or branched heteroalkyl radical, a cycloalkyl or cycloalkenyl radical, a heterocycloalkyl or heterocycloalkenyl radical, an aryl radical, an aralkyl radical, it being possible for the radicals to be substituted, in particular with one or more halogens or otherwise, their single multiple combined assemblies, and more generally any combination containing them in the form of single or repeated units,
and in particular the derivatives of general formula 2 such as for example 10-deacetylbaccatin III often have at least four free hydroxyls, one which is tertiary, at the 1-position, highly hindered and only esterifiable under drastic conditions, the other three, which are secondary, at the 7-, 10- and 13-positions, easier to esterify, which can, on the basis of their steric hindrance, be divided into two reactivity groups:
the first, at the 13-position, is relatively hardly reactive to esterification under standard reaction conditions (including, according to the literature, for the introduction of the side chain);
the second group, at the 7- and 10-positions, which is of interest to the subject of the present invention, can, in turn, be divided into two levels, which are different in a subtle way, of reactivities towards esterification or carbonation, slightly in favour of the hydroxyl at the 7-position.
It also emerges from research that the two hydroxylation sites present a case of allosteric interaction: the introduction of a hindered ester into one of the 7- or 10-positions modifies the steric availability of the other position.
The present invention therefore relates to a new process for the selective protection at the 7-position of 7,10-dihydroxytaxanes of general formula 3a above, using particular reaction conditions, simultaneously with the use of alkoxycarbonyl groups substituted at the 2-(or &bgr;-) position which are more hindered than 2,2,2-trichloroethoxycarbonyl (which remains nonselective under our particular reaction conditions), which are capable of being removed by a &bgr;-elimination mechanism (
Protecting Groups
, P. J. Kocienski, T
Chanteloup Luc
Chauveau Bruno
Corbin Christine
Dhal Robert
Guen Sonia Le
Aulakh Charanjit S.
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Societe d'Etude et de Recherche en Ingenierie Pharmaceutiqu
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