US2014080175A1PendingUtilityA1
Processes for preparing tubulysin derivatives and conjugates thereof
Est. expiryMar 29, 2032(~5.7 yrs left)· nominal 20-yr term from priority
Inventors:Iontcho Radoslavov VlahovHari Krishna R. SanthapuramPaul Joseph KleindlChristopher Paul LeamonFei You
C07F 7/188C07K 5/02C07D 213/71C07C 241/02C07D 417/12C07D 277/56C07D 213/76C07D 417/14C07F 7/1892C07K 7/02
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Claims
Abstract
The invention described herein pertains to processes for preparing tubulysin derivatives, conjugates of tubulysins, and intermediates therefore.
Claims
exact text as granted — not AI-modified1 . A process for preparing a compound of the formula
or a salt or solvate thereof, wherein
Ar 1 is optionally substituted aryl or optionally substituted heteroaryl;
Ar 2 is optionally substituted aryl or optionally substituted heteroaryl;
L is selected from the group consisting of
—(CR 2 ) p CR a R b —,
where p is an integer from about 1 to about 3, m is an integer from about 1 to about 4, and * indicates the points of attachment;
R a , R b , and R are each independently selected in each instance from the group consisting of hydrogen and alkyl; or any two of R a , R b , and R are taken together with the attached carbon atom(s) to form a carbocyclic ring;
R Ar represents 0 to 4 substituents selected from the group consisting of amino, or derivatives thereof, hydroxy or derivatives thereof, halo, thio or derivatives thereof, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof;
Y is acyloxy or R 12 O;
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;
R 12 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl or heteroarylalkyl, each of which is optionally substituted; 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) from a compound of formula (E), where X 1 is a leaving group
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 of formula D with a hydrolase enzyme or with a trialkyltin hydroxide, where R 8 is C1-C6 unbranched alkyl
or
the step of treating a compound of formula F1 with a non-basic fluoride reagent
or
the step of treating a compound of formula G1 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 H1
and
d) reacting the active ester intermediate with a compound of the formula I
or combinations 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) from a compound of formula E, where X 1 is a leaving group
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 a compound of formula D with a hydrolase enzyme or a trialkyltin hydroxide, where R 8 is C1-C6 unbranched alkyl
6 . The process of claim 1 comprising the step of treating a compound of formula G1 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 H1
and
d) reacting the active ester intermediate with a compound of the formula I
8 . The process of claim 1 wherein L is
9 . The process of claim 1 wherein O-L-S is
10 . The process of claim 1 wherein O-L-S is
11 . The process of claim 1 wherein Y is acyloxy.
12 . The process of claim 12 wherein R 2 is C1-C8 alkyl or C3-C8 cycloalkyl.
13 . The process of claim 1 wherein R 2 is CH 2 CH(CH 3 ) 2 , CH 2 CH 2 CH 3 , CH 2 CH 3 , CH═C(CH 3 ) 2 , or CH 3 .
14 . The process of claim 1 wherein R 3 is C1-C4 alkyl.
15 . The process of claim 1 wherein Ar 1 is optionally substituted aryl.
16 . The process of claim 1 wherein R 4 is C1-C8 alkyl or C3-C8 cycloalkyl.
17 . The process of claim 1 wherein R 5 is branched C3-C6 or C3-C8 cycloalkyl.
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 7 is C1-C6 alkyl.
20 . The process of claim 1 wherein Ar 2 is optionally substituted heteroaryl.Join the waitlist — get patent alerts
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