Method for preparing camptothecin derivatives

Details Method for preparing camptothecin derivatives Method for preparing camptothecin derivatives

2001-07-11

2004-04-06

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S362000, C546S048000

Reexamination Certificate

active

06716982

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a method of preparing camptothecin and camptothecin analogs employing chemical compounds that are useful as intermediates and to processes for the preparation of the intermediates.
BACKGROUND OF THE INVENTION
Camptothecin is a naturally occurring compound, found in
Camptotheca acuminata
. Camptothecin and camptothecin analogs have been found to have anti-leukemic and anti-tumor properties.
Camptothecin and camptothecin analogs can be synthesized using processes described in U.S. Pat. No. 4,894,456 to Wall et al. issued Jan. 16, 1990; U.S. Pat. No. 4,399,282 to Miyasaka, et al. issued Aug. 16, 1983; U.S. Pat. No. 4,399,276 to Miyasaka, et al. issued Aug. 16, 1983; U.S. Pat. No. 4,943,579 to Vishnuvajjala, et al. issued Jul. 24, 1990; European Patent Application 0 321 122 A2 filed by Smith Kline Becham Corporation, and published Jun. 21, 1989; U.S. Pat. No. 4,473,692 to Miyasaka, et al. issued Sep. 25, 1984; European Patent application No. 0 325 247 A2 filed by Kabushiki Kaisha Yakult Honsh, and published Jul. 26, 1989; European Patent application 0 556 585 A2 filed by Takeda Chemical Industries, and published Aug. 25, 1993; U.S. Pat. No. 4,981,968 to Wall, et al. issued Jan. 1, 1991; U.S. Pat. No. 5,049,668 to Wall, et al. issued Sep. 17, 1991; U.S. Pat. No. 5,162,532 to Comins, et al.; issued Nov. 10, 1992; U.S. Pat. No. 5,180,722 to Wall, et al. issued Jan. 19, 1993 and European Patent application 0 540 099 A1, filed by Glaxo Inc., and published May 5, 1993.
Previous methods used in the preparation of camptothecin and camptothecin analogs employ resolutions or chiral auxiliaries to obtain enantiomerically enriched intermediates. A problem with these methods is that a resolution necessitates discarding half of the racemic material and a chiral auxiliary requires utilizing stoichiometric amounts of a chiral subunit to stereoselectively install the chiral center.
A method which uses a process of catalytic asymmetric induction is described in U.S. patent application Ser. No. 08/237,081 and Fang et al., Journal of Organic Chemistry, 59(21), 6142-6143 (1994). One potential problem with such prior methods is that some of the chirally specific intermediates themselves may exhibit cell toxicity. Furthermore, the final step of the synthesis described in U.S. patent application Ser. No. 08/237,081 requires the use of a palladium catalyst which must subsequently be removed from the final drug substance by multiple recrystallizations. The potent cytotoxicity of camptothecin and some of its analogs requires that stringent safeguards be imposed during all the later steps of manufacturing to protect production personnel and the environment. Such safeguards increase the complexity and cost of manufacturing and handling camptothecin and its analogs.
An object of the present invention is a method for the preparation of camptothecin and its analogs wherein the chirality at the 20 position is not introduced until the penultimate manufacturing step. This would reduce the risk of accidental contamination of the environment and injury to the production worker, and hence, reduces the need for stringent safeguards, since handling and storage of highly biologically active material is minimized.
SUMMARY OF THE INVENTION
The present invention provides a method of preparing compounds of Formula (I) which comprises oxidizing compounds of Formula (II)
wherein:
R
1
and R
2
, which may be the same or different, are independently selected from hydrogen, lower alkyl, (C
3-7
)cycloalkyl, (C
3-7
)cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl, or alkoxy alkyl, or (—CH
2
NR
7
R
8
), wherein:
i) R
7
and R
8
, which may be the same or different, are independently selected from hydrogen, lower alkyl, (C
3-7
)cycloalkyl, (C
3-7
)cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl, or lower alkoxy lower alkyl; or
ii) R
7
represents hyrogen, lower alkyl, (C
3-7
)cycloalkyl, (C
3-7
) cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl, or lower alkoxy lower alkyl, and R
8
represents —COR
9
,
wherein:
R
9
represents hydrogen, lower alkyl, perhalo-lower alkyl, (C
3-7
)cycloalkyl, (C
3-7
)cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl, lower alkoxy, lower alkoxy lower alkyl; or
iii) R
7
represents hydrogen or lower alkyl; and R
8
represents diphenyl-methyl or —(CH
2
)
t
Ar
wherein:
t is 0 to 5 and
Ar represents phenyl, furyl, pyridyl, N-methylpyrrolyl, imidazolyl optionally substituted with one or more substituents selected from hydroxy, methyl, halogen, and amino; or
iv) R
7
and R
8
taken together with the linking nitrogen form a staturated 3 to 7 atom heterocyclic group of formula (IA)
wherein:
Y represents O, S, SO, SO
2
, CH
2
or NR
10
,
wherein:
R
10
represents hydrogen, lower alkyl, perhalo lower alkyl, aryl, aryl substituted with one or more substituents selected from lower alkyl, lower alkoxy, halogen, nitro, amino, lower alkyl amino, perhalo-lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl groups or
—COR
11
,
wherein:
R
11
represents hydrogen, lower alkyl, perhalo-lower alkyl, lower alkoxy, aryl, aryl substituted with one or more substituents selected from lower alkyl, perhalo-lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl groups; or
R
3
and R
4
are independently selected from hydrogen, lower alkyl, (C
3-7
)cycloalkyl, (C
3-7
)cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl, or alkoxy alkyl; or R
3
and R
4
taken together form a saturated 5 to 6 atom heterocyclic group of formula (IB)
wherein,
n represents the integer 1 or 2; or
R
3
represents —OCONR
12
R
13
,
wherein,
R
12
and R
13
, which may be the same or different, are independently selected from hydrogen, a substituted or unsubstituted alkyl group with 1-4 carbon atoms or a substituted or unsubstituted carbocyclic or heterocyclic group, with the proviso that when both R
12
and R
13
are substituted or unsubstituted alkyl groups, they may be combined together with the nitrogen atom, to which they are bonded, to form a heterocyclic ring which may be interrupted with —O—, —S— and/or >N—R
14
in which R
14
is hydrogen, a substituted or unsubstituted alkyl group with 1-4 carbon atoms or a substituted or unsubstituted phenyl group, and
R
5
represents hydrogen or alkyl, particularly methyl, and
R
6
represents hydrogen or alkyl, particularly hydrogen, and
pharmaceutically acceptable salts thereof.
The present invention further provides a method of preparing compounds of Formula (I) which comprises dihydroxylating a compound of Formula (II) and subsequent oxidation to yield a compound of Formula (I).
In addition to a method of preparing compounds of Formula (I) from compounds of Formula (II), other aspects of the invention include the compounds of Formula (II) and various intermediates useful in the formation of compounds of Formula (I) and (II). Other aspects and advantages of the present invention will become apparent from a review of the detailed description below.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “loweralkyl” means, a linear or branched alkyl group with 1-8, preferably 1-4 carbon atoms, such as, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, hexyl and octyl. This definition also applies to a loweralkyl moiety in the loweralkoxy, loweralkylthio, and di(loweralkyl)amino groups. Thus, examples of loweralkoxy groups are methoxy, ethoxy, propoxy, sec-butoxy, and isohexoxy: examples of loweralkylthio groups are methylthio, ethylthio, tert-butylthio, and hexylthio, and examples of di(loweralkyl)amino groups are dimethylamino, diethylamino, diisopropylamino, di(n-butyl)amino, and dipentylamino.
The terms “halo” and “halogen” as used herein refer to a substitutent which may be fluoro, chloro, bromo, or iodo. The term “triflate” as used herein refers to trifluoromethanesulfonate. The designation “C” as used herein means centigrade. The term “ambient temperature” as used herein means from about 20° C. to about 30° C.
Compounds of the present invention may have 1 or more asymmetric car

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