Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-08-24
2000-11-07
Lambkin, Deborah C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
549519, C07D30338, C07D30102
Patent
active
061439096
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Neoplastic diseases, characterized by the proliferation of cells not subject to the normal control of cell growth, are a major cause of death in humans and other mammals. Clinical experience in cancer chemotherapy has demonstrated that new and more effective drugs are desirable to treat these diseases. Such clinical experience has also demonstrated that drugs which disrupt the microtubule system of the cytoskeleton can be effective in inhibiting the proliferation of neoplastic cells.
Cryptophycin compounds can now be prepared using a total synthetic process; however, many of the useful cryptophycin compounds contain a labile epoxide group. Barrow, R. A. et al., J. Am. Chem. Soc. 117, 2479 (1995). Applicants have discovered that the beta-epoxide can be particularly desired. However, in the Barrow et al. synthesis of some of the cryptophycin compounds of formula (I) below, the epoxidation is performed in the last step which provides only a 2:1 selectivity for the desired epoxide. Furthermore, the diasteromers are difficult to separate at this stage. While it would be desirable to epoxidize an earlier intermediate in the process, epoxides are sensitive to a number of reaction conditions. Moreover, there remains a need for processes with greater stereoselectivity to avoid difficult diastereomeric separations.
The present invention provides a much desired novel and efficient method for preparing cryptophycin compounds having an epoxide functionality. The epoxidation is selective and may be employed at various steps in the overall synthetic process.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to a process for preparing a compound of the formula ##STR1## wherein G is C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, or Ar; heteroaromatic group; together form a second bond between C-13 and C-14; alkyl; or C.sub.2 -C.sub.6 alkynyl, --(CH.sub.2).sub.m --(C.sub.3 -C.sub.5)cycloalkyl or benzyl, wherein m is the integer one to three; (C.sub.3 -C.sub.8)cycloalkyl, substituted (C.sub.3 -C.sub.8)cycloalkyl, a heteroaromatic or substituted heteroaromatic group or a group of formula (IA), (IB) or (IC): ##STR2## R.sup.6a, R.sup.6b, and R.sup.6c independently are H, halo or OR.sup.18 ; R.sup.15, R.sup.16, and R.sup.17 independently are hydrogen, halo, (C.sub.1 -C.sub.6)alkyl, OR.sup.18, O-aryl, NH.sub.2, NR.sup.18 R.sup.19, NO.sub.2, OPO.sub.4 H.sub.2, (C.sub.1 -C.sub.6 alkoxy)phenyl, S-benzyl, CONH.sub.2, CO.sub.2 H, PO.sub.3 H.sub.2, SO.sub.2 R.sup.23, or Z'; acceptable salt thereof; ##STR3## wherein G, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.14 and R.sup.50 are as defined above and Y is Y' or S; with an oxidant and a chiral ketone to form a compound of formula (I); and optionally forming a pharmaceutically acceptable salt thereof.
This invention further comprises a process for preparing a compound of the formula ##STR4## wherein G is C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, or Ar; heteroaromatic group; together form a second bond between C-13 and C-14; SR.sup.81 ; formula ##STR5## R.sup.7 and R.sup.8 are each independently hydrogen or C.sub.1 -C.sub.6 alkyl; or C.sub.2 -C.sub.6 alkynyl, --(CH.sub.2).sub.m --(C.sub.3 -C.sub.5)cycloalkyl or benzyl, wherein m is the integer one to three; -C.sub.3 alkyl; (C.sub.3 -C.sub.8)cycloalkyl, substituted (C.sub.3 -C.sub.8)cycloalkyl, a heteroaromatic or substituted heteroaromatic group or a group of formula (IA), (IB) or (IC): ##STR6## R.sup.6a, R.sup.6b, and R.sup.6c independently are H, (C.sub.1 -C.sub.6)alkyl, halo NR.sup.18 R.sup.19 or OR.sup.18 ; -C.sub.6)alkyl, OR.sup.18, O-aryl, NH.sub.2, NR.sup.18 R.sup.19, NO.sub.2, OPO.sub.4 H.sub.2, (C.sub.1 -C.sub.6 alkoxy)phenyl, S-benzyl, CONH.sub.2, CO.sub.2 H, PO.sub.3 H.sub.2, SO.sub.2 R.sup.23, or Z'; benzyl; and acceptable salt thereof; with the proviso that when R.sup.83 is --CH.sub.2 SR.sup.81, R.sup.30 is not hydrogen or an alcohol protecting group; with the further pr
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Hoard David Warren
Moher Eric David
Norman Bryan Hurst
Patel Vinod Francis
Eli Lilly and Company
Engelmann John H.
Lambkin Deborah C.
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