Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2002-07-16
2003-10-07
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S822000, C568S838000, C568S375000, C568S374000, C568S361000, C568S338000, C549S512000, C549S513000
Reexamination Certificate
active
06630609
ABSTRACT:
SUMMARY OF THE INVENTION
The present invention is directed to a process for the preparation of baccatin III, taxol, docetaxel and their analogs from borneol (1) and camphor (2), commonly known articles of commerce.
Processes for the total synthesis of taxol and other tetracyclic taxanes from commodity chemicals have been proposed. For example, in U.S. Pat. No. 5,405,972, Holton et al. disclose a process for the synthesis of taxol and other tetracyclic taxanes from &bgr;-patchouline epoxide which, in turn, may be obtained from borneol (1) and camphor (2). Yields obtained by these processes, however, leave some room for improvement.
Leriverend and Conia (
Bull. Soc. Chim. Fr
., 1970, 1060) observed that diol 4 (which is readily prepared from either camphor or borneol) when heated to 220° C. for a period of one hour rearranged to provide a mixture of ketones 5 and 6 in a ratio of 1:2. Ketone 5 is of great utility in the synthesis of taxanes.
The preparation of diol 4 and ketones 5 and 6 is illustrated in Reaction Scheme 1.
Briefly, therefore, the present invention is directed to a process for the preparation of ketone 5 in relatively high yield and without contamination with ketone 6. The process comprises treating a compound having the formula:
with a base and a silylating agent to form a compound having the formula:
The present invention is further directed to a process for converting ketone 5 into taxol, docetaxel, and other taxanes. According to this process, a derivative of ketone 5 having the formula:
is treated with an alkyl metal species, preferably tert-butyllithium, or is treated with a Lewis acid, preferably TMSOTf, in the presence of a tertiary amine base, preferably triethylamine, to form a compound having the formula:
wherein P
2
is hydrogen or a hydroxyl protecting group. The process for converting ketone 5 into taxol, docetaxel, and other taxanes may additionally comprise treating a compound having the formula:
with a Lewis acid, preferably TMSOTf, in the presence of a tertiary amine base, preferably triethyl amine, to form a compound having the formula:
wherein P
2
and P
10
are independently hydrogen or a hydroxyl protecting group.
The present invention is additionally directed to the following intermediates having the formulae
wherein P
2
, P
9
, P
10
and P
13
are independently selected from hydrogen and hydroxy protecting groups. Compounds containing one or more hydroxy protecting groups can be converted to their hydroxy group analogs by removing such hydroxy protecting groups using standard methods. The compounds identified above are key intermediates in the synthesis of baccatin III, 1-deoxy baccatin III, taxol, 1-deoxy taxol, docetaxel, 1-deoxy docetaxel, and the analogs of these compounds.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides a process for the preparation of ketone 5 in high yield relative to its isomer 6. When diol 4 is treated with a base in the presence of a silylating agent, ketone 5 can be obtained in greater than 95% yield. The base employed is preferably stronger than an alkoxide base. More preferably, the base is a hydride base or an amide base. Still more preferably, the base is potassium hydride or potassium hexamethyldisilazide. The base is preferably nonreactive with the silylating agent selected for the reaction.
Silylating agents for the reaction include those compounds comprising the group —SiR
1
R
2
R
3
wherein R
1
, R
2
and R
3
are independently substituted or unsubstituted C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, monocyclic aryl or monocyclic heteroaryl. Such silylating agents may further comprise a hydride or triflate group, for example tri(hydrocarbyl)silyl halides and tri(hydrocarbyl)silyl triflates. The hydrocarbon moieties of these silylating agents may be substituted or unsubstituted and preferably are substituted or unsubstituted alkyl or aryl. Trialkylsilyl halides are more preferred with alkyl groups containing from one to four carbon atoms. Still more preferably, the silylating agent is triethylsilyl chloride. Ethereal solvents are preferred for the reaction, with THF being the more preferred solvent.
While the temperature at which the reaction is carried out is not narrowly critical, the temperature may affect the overall yield of the reaction. Preferably, the temperature of the reaction is maintained below about 50° C.; more preferably, the temperature is maintained at or below about 25° C.; even more preferably, the temperature initially is maintained at or below about 0° C. and subsequently is maintained at or below about 25° C. As illustrated in the Examples, these latter conditions produced ketone 5 in 96% yield.
Likewise, the sequence of addition of diol 4, the base and the silylating agent is flexible. For example, diol 4, the base and the silylating agent may be combined at the beginning of the process and reacted in essentially a single step, or these reagents may be combined as described in the Examples.
The reagents for the foregoing reaction (as well as the reagents for the reactions subsequently discussed in this application) are preferably provided in approximately stoichiometric amounts, although various ratios of the reagents can be effectively employed.
Without being bound to any specific theory, it is believed based upon the evidence to date that the base operates to deprotonate the two hydroxy groups of diol 4. The less-sterically-hindered deprotonated hydroxy group (which corresponds to the front hydroxy group of the structure of diol 4 illustrated in Reaction Scheme 1) then reacts with the silylating agent to form a protected hydroxy group. The other deprotonated hydroxy group (which corresponds to the rear hydroxy group of the structure of diol 4 illustrated in Reaction Scheme 1) does not react with the silylating agent. The protected diol 4 then undergoes the oxy-Cope rearrangement to provide a nine-membered ring containing a silyl enol ether and an enolate. Upon the addition of water the enolate is protonated and the subsequent aldol condensation is directed by the position of the silyl enol ether to provide ketone 5.
Ketone 5 can be further converted to other useful taxane synthetic intermediates as shown below.
As shown in reaction scheme 2, treatment of ketone 5 with an amide base, preferably an alkali metal amide base and more preferably LHMDS, in an ethereal solvent, preferably THF, and then with a hydroxylating agent, preferably an oxaziridine and more preferably phenylsulfonyl oxaziridine, provides allylic alcohol 7. Allylic alcohol 7 in the presence of an epoxidizing agent, preferably a peroxy acid and more preferably m-chloroperbenzoic acid, is converted to epoxide 8. Epoxide 8 can be reduced stereoselectively to diol 9 (P
2
=H), using a hydride reducing agent, preferably a borohydride and more preferably sodium borohydride. The secondary hydroxyl group of 9 can be protected with any of a variety of protecting groups, using standard methods for their attachment. Treatment of 9 with a Lewis acid in the presence of a tertiary amine base, preferably triethyl amine, causes its rearrangement to give 10. In general, the Lewis acids that can be used include triflates and halides of elements of groups IB, IIB, IIIB, IVB, VB, VIB, VIIB, VIII, IIIA, IVA, lanthanides, and actinides (American Chemical Society format), with a preferred Lewis acid being TMSOTf. The second secondary hydroxyl group of 10 can be protected with any of a variety of protecting groups so that P
10
and P
2
may be the same or different and readily chemically distinguishable from each other.
Alternatively, as shown in reaction scheme 3, treatment of ketone 5 with a hydride reducing agent, preferably a borohydride and more preferably sodium borohydride, in the presence of a Lewis acid, preferably a lanthanide metal halide or triflate and more preferably a samarium or cerium halide, selectively furnishes allylic alcohol 11, which undergoes epoxidation from th
Gharbaoui Tawfik
Holton Robert A.
Reboul Vincent
Vu Phong
Florida State University
Richter Johann
Senniger Powers Leavitt & Roedel
Witherspoon Sikarl A.
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