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US 6,143,909 AGranted
Selective epoxidation process for preparing pharmaceutical compounds
AssigneeEli Lilly and Company
InventorsDavid Warren Hoard, Eric David Moher, Vinod Francis Patel, Bryan Hurst Norman
Life of this patent
Estimating the term…
Abstract
Cryptophycin compounds possessing a .beta.-epoxy moiety may be made with high stereoselectivity at various steps in the overall synthetic process. This invention also provides novel intermediates useful in preparing Cryptophycin compounds.
Claims40
A process for preparing a compound of the formula ##STR71## 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;
- Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group;
- R.sup.3 is C.sub.1 -C.sub.6 alkyl;
- R.sup.4 and R.sup.5 are each hydrogen;
- or R.sup.4 and R.sup.5 taken together form a second bond between C-13 and C-14;
- R.sup.7 and R.sup.8 are each independently hydrogen or C.sub.1 -C.sub.6 alkyl;
- or
- R.sup.7 and R.sup.8 taken together form a cyclopropyl or cyclobutyl ring;
- R.sup.9 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, 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;
- R.sup.10 is hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.11 is hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl or benzyl;
- R.sup.14 is hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.50 is hydrogen or (.dbd.O);
- Y is CH, O, NH, SO, SO.sub.2 or (C.sub.1 -C.sub.3)alkylamino;
- R.sup.6 is C.sub.1 -C.sub.6 alkyl, substituted (C.sub.1 -C.sub.6)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):
- ##STR72## 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';
- R.sup.18 and R.sup.19 independently are hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.23 is hydrogen or (C.sub.1 -C.sub.3)alkyl;
- Z is --(CH.sub.2).sub.11 -- or (C.sub.3 -C.sub.5)cycloalkyl;
- n is 0, 1, or 2;
- and
- Z' is an aromatic or substituted aromatic group;
- or a pharmaceutically acceptable salt thereof;
- comprising epoxidizing a compound of the formula ##STR73## 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.
23 more elements
A process for preparing a compound of the formula 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;
- Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group;
- R.sup.3 is C.sub.1 -C.sub.6 alkyl;
- R.sup.4 and R.sup.5 are each hydrogen;
- or R.sup.4 and R.sup.5 taken together form a second bond between C-13 and C-14;
- R.sup.83 is hydrogen, C.sub.1 -C.sub.6 alkyl, trichloroethyl, or --CH.sub.2 SR.sup.81 ;
- R.sup.30' is hydrogen, an alcohol protecting group, or a group of the formula ##STR75## R.sup.7 and R.sup.8 are each independently hydrogen or C.sub.1 -C.sub.6 alkyl;
- or
- R.sup.7 and R.sup.8 taken together form a cyclopropyl or cyclobutyl ring;
- R.sup.9 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, 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;
- R.sup.10 is hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.11 is hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl or benzyl;
- R.sup.14 is hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.50 is hydrogen or (.dbd.O);
- Y is CH, O, NR.sup.12, S, SO, SO.sub.2, wherein R.sup.12 is H or C.sub.1 -C.sub.3 alkyl;
- R.sup.6 is C.sub.1 -C.sub.6 alkyl, substituted (C.sub.1 -C.sub.6)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):
- ##STR76## 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 ;
- 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';
- R.sup.18 and R.sup.19 independently are hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.23 is hydrogen or (C.sub.1 -C.sub.3)alkyl;
- Z is --(CH.sub.2).sub.n -- or (C.sub.3 -C.sub.5)cycloalkyl;
- n is 0, 1, or 2;
- and
- Z' is an aromatic or substituted aromatic group;
- R.sup.81 is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.8 cycloalkyl, phenyl or benzyl;
- and
- R.sup.82 is a base labile protecting group;
- or a pharmaceutically 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;
- comprising epoxidizing a compound of the formula ##STR77## wherein G, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.14, R.sup.30' and R.sup.83 are as defined above;
- with an oxidant and a chiral ketone to form a compound of formula (II);
- and optionally forming a pharmaceutically acceptable salt thereof.
29 more elements
A compound of the formula ##STR98## 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;
- Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group;
- R.sup.3 is C.sub.1 -C.sub.6 alkyl;
- R.sup.4 and R.sup.5 are each hydrogen;
- or R.sup.4 and R.sup.5 taken together form a second bond between C-13 and C-14;
- R.sup.14 is hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.6 is C.sub.1 -C.sub.6 alkyl, substituted (C.sub.1 -C.sub.6)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):
- ##STR99## 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';
- R.sup.18 and R.sup.19 independently are hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.23 is hydrogen or (C.sub.1 -C.sub.3)alkyl;
- Z is --(CH.sub.2).sub.n -- or (C.sub.3 -C.sub.5)cycloalkyl;
- n is 0, 1, or 2;
- and
- Z' is an aromatic or substituted aromatic group;
- or a pharmaceutically acceptable salt thereof.
12 more elements
A compound of the formula 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;
- Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group;
- R.sup.3 is C.sub.1 -C.sub.6 alkyl;
- R.sup.4 and R.sup.5 are each hydrogen;
- or R.sup.4 and R.sup.5 taken together form a second bond between C-13 and C-14;
- R.sup.7 and R.sup.8 are each independently hydrogen or C.sub.1 -C.sub.6 alkyl;
- or
- R.sup.7 and R.sup.8 taken together form a cyclopropyl or cyclobutyl ring;
- R.sup.9 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, 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;
- R.sup.10 is hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.11 is hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl or benzyl;
- R.sup.14 is hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.50 is hydrogen or (.dbd.O);
- Y is CH, O, NH, S, SO, SO.sub.2 or (C.sub.1 -C.sub.3)alkylamino;
- R.sup.6 is C.sub.1 -C.sub.6 alkyl, substituted (C.sub.1 -C.sub.6)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):
- ##STR101## 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.19 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';
- R.sup.18 and R.sup.19 independently are hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.23 is hydrogen or (C.sub.1 -C.sub.3)alkyl;
- Z is --(CH.sub.2).sub.n -- or (C.sub.3 -C.sub.5)cycloalkyl;
- n is 0, 1, or 2;
- Z' is an aromatic or substituted aromatic group;
- and
- R.sup.82 is a base labile protecting group;
- or a pharmaceutically acceptable salt thereof.
22 more elements
A compound of the formula 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;
- Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group;
- R.sup.3 is C.sub.1 -C.sub.6 alkyl;
- R.sup.4 and R.sup.5 are each hydrogen;
- or R.sup.4 and R.sup.5 taken together form a second bond between C-13 and C-14;
- R.sup.7 and R.sup.8 are each independently hydrogen or C.sub.1 -C.sub.6 alkyl;
- or
- R.sup.7 and R.sup.8 taken together form a cyclopropyl or cyclobutyl ring;
- R.sup.9 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, 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;
- R.sup.10 is hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.11 is hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl or benzyl;
- R.sup.14 is hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.50 is hydrogen or (.dbd.O);
- Y is CH, O, NH, S, SO, SO.sub.2 or (C.sub.1 -C.sub.3)alkylamino;
- R.sup.6 is C.sub.1 -C.sub.6 alkyl, substituted (C.sub.1 -C.sub.6)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):
- ##STR103## 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';
- R.sup.18 and R.sup.19 independently are hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.23 is hydrogen or (C.sub.1 -C.sub.3)alkyl;
- Z is --(CH.sub.2).sub.n -- or (C.sub.3 -C.sub.5)cycloalkyl;
- n is 0, 1, or 2;
- and
- Z' is an aromatic or substituted aromatic group;
- or a pharmaceutically acceptable salt thereof.
21 more elements
A process for preparing a compound of the formula 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;
- Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group;
- R.sup.3 is C.sub.1 -C.sub.6 alkyl;
- R.sup.4 and R.sup.5 are each hydrogen;
- or R.sup.4 and R.sup.5 taken together form a second bond between C-13 and C-14;
- R.sup.7 and R.sup.8 are each independently hydrogen or C.sub.1 -C.sub.6 alkyl;
- or
- R.sup.7 and R.sup.8 taken together form a cyclopropyl or cyclobutyl ring;
- R.sup.9 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, 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;
- R.sup.10 is hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.11 is hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl or benzyl;
- R.sup.14 is hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.50 is hydrogen or (.dbd.O);
- Y is CH, O, NR.sup.12, S, SO, SO.sub.2, wherein R.sup.12 is H or C.sub.1 -C.sub.3 alkyl;
- R.sup.6 is C.sub.1 -C.sub.6 alkyl, substituted (C.sub.1 -C.sub.6)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):
- ##STR105## 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 ;
- 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';
- R.sup.18 and R.sup.19 independently are hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.23 is hydrogen or (C.sub.1 -C.sub.3)alkyl;
- R.sup.81 is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.8 cycloalkyl, phenyl or benzyl;
- R.sup.82 is a base labile protecting group;
- Z is --(CH.sub.2).sub.n -- or (C.sub.3 -C.sub.5)cycloalkyl;
- n is 0, 1, or 2;
- q is an integer 1 or 2;
- and
- Z' is an aromatic or substituted aromatic group;
- or a pharmaceutically acceptable salt thereof;
- comprising oxidizing a compound of the formula ##STR106## 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, R.sup.50, R.sup.81, R.sup.82 and Y are as defined above, with an oxidizing agent to form a compound of formula (9) and optionally forming a pharmaceutically acceptable salt of a compound of formula (9).
25 more elements
Dependencies are inferred from the claim text.