Taxane compounds, compositions and methods
The present invention provides a method for the preparation of orally available pentacyclic taxane compounds, as well as intermediates useful in their preparation.
1. A compound having a formula
2. A method of making a taxane compound comprising coupling a taxane side chain precursor compound to a C13 hydroxyl group of the compound of claim 1 to produce a protected taxane reaction product, deprotecting the protected taxane reaction product, and isolating the taxane compound.
3. The method of claim 2 , wherein the taxane side chain precursor compound has a formula
wherein R 2 is an alkoxy group having from 1 to 6 carbon atoms or a halogen atom and R 33 is a protected hydroxyl group.
4. The method of claim 3 , wherein the hydroxyl group is protected by a triisopropylsilyl (TIPS) or 2-methoxy propyl (MOP) group.
5. The method of claim 3 , wherein R 2 is fluorine.
6. The method of claim 5 , wherein fluorine is at the 3-position of pyridine.
7. The method of claim 3 , wherein the side chain precursor compound has a formula
wherein Me is methyl and BOC is tert-butoxycarbonyl.
8. The method of claim 2 , wherein the compound according to claim 1 is derived from a compound having a formula (Ib):
or from a compound having a formula (III):
9. The method of claim 8 , wherein the compound having the formula (III) or the compound having a formula (Ib) is derived from a compound having a formula (VII):
10. The method of claim 9 , wherein the compound having the formula (VII) is converted to
11. The method of claim 9 , wherein the compound having the formula (VII) is derived from a compound having a formula (X):
or from a compound having a formula (IX):
12. The method of claim 2 , wherein the compound according to claim 1 is synthesized by a process comprising:
formylating C10 of 10-DAB III to produce a first intermediate comprising a C10 formyl ester;
reacting a C7 hydroxyl of the first intermediate with triflic anhydride to produce a second intermediate;
forming a C6-7 double bond in the second intermediate and hydrolyzing the C10 formyl ester to produce a third intermediate;
reducing a C9 ketone of the third intermediate to form a diol compound having hydroxyls at C9 and C10;
forming a C9-C10 cyclic acetal from the diol, wherein the cyclic acetal is attached to a terminal olefin group;
oxidatively cleaving the terminal olefin group to form an aldehyde;
reductively aminating the aldehyde; and
hydrogenating the C6-7 double bond.
13. The method of claim 2 , wherein the compound according to claim 1 is synthesized by a process comprising:
formylating C10 of 10-DAB III to produce a first intermediate comprising a C10 formyl ester;
reacting a C7 hydroxyl of the first intermediate with triflic anhydride to produce a second intermediate;
forming a C6-7 double bond in the second intermediate and hydrolyzing the C10 formyl ester to produce a third intermediate;
reducing a C9 ketone of the third intermediate to form a diol compound having hydroxyls at C9 and C10;
hydrogenating the C6-7 double bond;
forming a C9-C10 cyclic acetal from the diol, wherein the cyclic acetal is attached to a terminal olefin group;
oxidatively cleaving the terminal olefin group to form an aldehyde; and
reductively aminating the aldehyde.
14. The method of claim 2 , wherein the compound according to claim 1 is synthesized by a process comprising:
reacting a C7 hydroxyl of 10-DAB III with triflic anhydride to produce a first intermediate;
forming a C6-7 double bond in the first intermediate by base elimination;
reducing the C6-7 double bond to produce a reduced first intermediate;
reducing a C9 ketone of the reduced first intermediate to form a diol compound having hydroxyls at C9 and C10;
forming a cyclic acetal from the diol, wherein the cyclic acetal is attached to a terminal olefin group;
oxidatively cleaving the terminal olefin group to an aldehyde; and
reductively aminating the aldehyde.
15. The method of claim 2 , wherein the compound according to claim 1 is synthesized by a process comprising:
reducing a C9 ketone of 10-DAB III to produce a triol first intermediate;
forming a C9-C10 cyclic acetal from the triol first intermediate to produce a second intermediate, wherein the cyclic acetal is attached to a terminal olefin group;
reacting a C7 hydroxyl of the second intermediate with triflic anhydride;
forming a C6-C7 double bond by base elimination;
oxidatively cleaving the terminal olefin group to an aldehyde;
reductively aminating the aldehyde; and
hydrogenating the C6-C7 double bond.
16. The method of claim 2 , wherein the compound according to claim 1 is synthesized by a process comprising:
reducing a C9 ketone of 10-DAB III to produce a triol first intermediate having hydroxyls at C9 and C10;
reacting a C7 hydroxyl of the first intermediate with triflic anhydride to produce a second intermediate;
forming a C6-C7 double bond in the second intermediate by base elimination to produce a third intermediate;
forming a C9-C10 cyclic acetal from the diol of the third intermediate, wherein the cyclic acetal is attached to a terminal olefin group;
oxidatively cleaving the terminal olefin group to an aldehyde;
reductively aminating the aldehyde; and
hydrogenating the C6-C7 double bond.
17. The method of claim 11 , wherein 10-DAB III is converted to the compound represented by formula (IX) by reacting a C7 hydroxyl of 10-DAB III with triflic anhydride and treating with base to form a C6-C7 double bond.
18. The method of claim 2 , wherein the side chain precursor compound is coupled to C13 using a hindered soluble alkaline metal base.
19. The method of claim 2 , further comprising converting the taxane compound to a pharmaceutically acceptable acid salt form.
20. The method of claim 2 , wherein the taxane compound is tesetaxel.