Processes for preparing tubulysins
Tubulysins are a series of naturally occurring cytotoxic agents that are of interest as anticancer therapeutic agents. Processes and intermediates useful for preparing naturally occurring and non-naturally occurring tubulysins and analogs and derivatives thereof are described.
1. A process for preparing a compound of the formula
or a pharmaceutically acceptable salt thereof;
wherein
Ar 1 is 4-hydroxyphenyl;
R 1 is hydrogen, alkyl, arylalkyl or a pro-drug forming group;
R 2 is selected from the group consisting of optionally substituted alkyl and optionally substituted cycloalkyl;
R 3 is optionally substituted alkyl;
R 4 is optionally substituted alkyl or optionally substituted cycloalkyl;
R 5 and R 6 are each independently selected from the group consisting of optionally substituted alkyl and optionally substituted cycloalkyl;
R 7 is optionally substituted alkyl; and
n is 1, 2, 3, or 4;
wherein the process comprises
the step of treating a compound of formula A with triethylsilyl chloride and imidazole in an aprotic solvent, where R 8 is C1-C6 unbranched alkyl
or
the step of treating a compound of formula B with a base and a compound of the formula ClCH 2 OC(O)R 2 in an aprotic solvent at a temperature from about −78° C. to about 0° C.; wherein the molar ratio of the compound of the formula ClCH 2 OC(O)R 2 to the compound of formula B from about 1 to about 1.5, where R 8 is C1-C6 unbranched alkyl
or
the steps of
a) preparing a compound of formula (E1) where X 1 is a leaving group from a compound of formula E
and
b) treating a compound of formula C under reducing conditions in the presence of the compound of formula E1, where R 8 is C1-C6 unbranched alkyl
or
the step of treating compound D with a hydrolase enzyme, where R 8 is C1-C6 unbranched alkyl
or
the step of treating the silyl ether of compound F with a non-basic fluoride reagent
or
the step of treating a compound of formula G with an acylating agent of formula R 4 C(O)X 2 , where X 2 is a leaving group
or
the steps of
c) forming an active ester intermediate from a compound of formula H
and
d) reacting the active ester intermediate with a compound of the formula I
or a combination thereof.
2. The process of claim 1 comprising the step of treating a compound of formula A with triethylsilyl chloride and imidazole in an aprotic solvent, where R 8 is C1-C6 unbranched alkyl
3. The process of claim 1 comprising the step of treating a compound of formula B with a base and a compound of the formula ClCH 2 OC(O)R 2 in an aprotic solvent at a temperature from about −78° C. to about 0° C.; wherein the molar ratio of the compound of the formula ClCH 2 OC(O)R 2 to the compound of formula B from about 1 to about 1.5, where R 8 is C1-C6 unbranched alkyl
4. The process of claim 1 comprising the steps of
a) preparing a compound of formula (E1) where X 1 is a leaving group from a compound of formula E
and
b) treating a compound of formula C under reducing conditions in the presence of the compound of formula E1, where R 8 is C1-C6 unbranched alkyl
5. The process of claim 1 comprising the step of treating compound D with a hydrolase enzyme, where R 8 is C1-C6 unbranched alkyl
6. The process of claim 1 comprising the step of treating a compound of formula G with an acylating agent of formula R 4 C(O)X 2 , where X 2 is a leaving group
7. The process of claim 1 comprising the steps of
c) forming an active ester intermediate from a compound of formula H
and
d) reacting the active ester intermediate with a compound of the formula I
8. The process of claim 1 wherein R 1 is hydrogen, benzyl, or C1-C4 alkyl.
9. The process of claim 1 wherein R 1 is hydrogen.
10. The process of claim 1 wherein R 2 is C1-C8 alkyl or C3-C8 cycloalkyl.
11. The process of claim 1 wherein R 2 is n-butyl.
12. The process of claim 1 wherein R 3 is C1-C4 alkyl.
13. The process of claim 1 wherein R 3 is methyl.
14. The process of claim 1 wherein R 4 is C1-C8 alkyl or C3-C8 cycloalkyl.
15. The process of claim 1 wherein R 4 is methyl.
16. The process of claim 1 wherein R 5 is branched C3-C6 or C3-C8 cycloalkyl.
17. The process of claim 1 wherein R 5 is iso-propyl.
18. The process of claim 1 wherein R 6 is branched C3-C6 or C3-C8 cycloalkyl.
19. The process of claim 1 wherein R 5 is sec-butyl.
20. The process of claim 1 wherein R 7 is C1-C6 alkyl.
21. The process of claim 1 wherein R 7 is methyl.