Process and intermediates for making tubulysin analogs
AssigneeBristol-Myers Squibb Company
InventorsAdrian ORTIZ, Carlos A. GUERRERO, Bin ZHENG, Jason J. ZHU, Michael Anthony SCHMIDT, Michael R. LUZUNG, Martin D. EASTGATE
Life of this patent
Estimating the term…
Abstract
An improved process for making a compound B of the structure wherein n, R1, R2, and R3 are as defined in the specification. Compound B can be used to make tubulysin analogs that are, in turn, useful as anti-cancer agents, particularly when deployed in an antibody-drug conjugate.
Claims19
A process for making a compound 21, or a salt thereof
- comprising the steps of
- (a) combining a compound 18
- with a compound 19
- Li—≡—PG 19
- in a reaction medium and allowing the two compounds to react with each other;
- (b) then adding to the reaction medium a compound 20
- R3—X1 20
- (c) then adding a de-chelating agent to the reaction medium to produce a compound 21;
- and
- (d) optionally adding a primary or secondary alcohol and an anion source to the reaction medium to produce a salt of compound 21;
- wherein
- R0 is C1-C4 alkyl;
- R3 is Me, Et, or n-Pr;
- X1 is Cl, Br, I triflate, mesylate, or tosylate;
- and
- PG is a silyl protective group.
A process for making a compound 23
- comprising reacting a compound 21
- with a compound 22
- in the presence of a haloalkyl aluminum compound to form compound 23;
- wherein
- n is 0, 1, or 2;
- R1 is H or C1-C4 alkyl;
- R2 is Me, Et, n-Pr, i-Pr, or (S) sec-butyl;
- R3 is Me, Et, or n-Pr;
- PG is a silyl protective group;
- and
- LG is a leaving group.
A process for making a compound 26
- comprising regioselectively hydrating a compound having a structure according to formula 25
- wherein
- n is 0, 1, or 2;
- R1 is H or C1-C4 alkyl;
- R2 is Me, Et, n-Pr, i-Pr, or (S) sec-butyl;
- R3 is Me, Et, or n-Pr;
- and
- X2 is C1-C3 alkyl, aryl or benzyl;
- the aryl or benzyl group being optionally substituted with Cl, Br, Me, Et, CN, NO2 or O(C1-C3 alkyl).
A process for making a compound 27
- comprising enantioselectively hydrogenating a compound 26
- in the presence of an asymmetric hydrogenation catalyst;
- wherein
- n is 0, 1, or 2;
- R1 is H or C1-C4 alkyl;
- R2 is Me, Et, n-Pr, i-Pr, or (S) sec-butyl;
- R3 is Me, Et, or n-Pr;
- and
- X2 is C1-C3 alkyl, aryl or benzyl;
- the aryl or benzyl group being optionally substituted with Cl, Br, Me, Et, CN, NO2 or O(C1-C3 alkyl).
A compound having a structure according to formula 21a″
- wherein PG is a silyl protecting group, preferably trimethyl silyl, triethyl silyl, triisopropyl silyl, t-butyldiphenyl silyl, or t-butyldimethyl silyl;
- or a salt thereof.
A compound having a structure according to formula 23a
A compound having a structure according to formula 25
- wherein
- n is 0, 1, or 2;
- R1 is H or C1-C4 alkyl;
- R2 is Me, Et, n-Pr, i-Pr, or (S) sec-butyl;
- R3 is Me, Et, or n-Pr;
- and
- X2 is C1-C3 alkyl, aryl or benzyl;
- the aryl or benzyl group being optionally substituted with Cl, Br, Me, Et, CN, NO2 or O(C1-C3 alkyl).
A compound having a structure according to formula 26
- wherein
- n is 0, 1, or 2;
- R1 is H or C1-C4 alkyl;
- R2 is Me, Et, n-Pr, i-Pr, or (S) sec-butyl;
- R3 is Me, Et, or n-Pr;
- and
- X2 is C1-C3 alkyl, aryl or benzyl;
- the aryl or benzyl group being optionally substituted with Cl, Br, Me, Et, CN, NO2 or O(C1-C3 alkyl).
A process for making a compound B,
- comprising the steps of:
- (a) preparing a compound 21 or a salt thereof
- from compounds 18, 19 and 20
- (b) reacting compound 21 with a compound 22
- in the presence of a haloalkyl aluminum compound to produce compound 23
- (c) removing the group PG from compound 23 to form a compound 23′
- (d) coupling compound 23′ and a compound 24
- to produce compound 25
- (e) regioselectively hydrating compound 25 to produce a compound 26
- (f) enantioselectively reducing compound 26 to produce a compound 27
- and
- (g) hydrolyzing the ester group and acetylating the hydroxyl group in compound 27 to produce compound B;
- wherein
- n is 0, 1, or 2;
- R0 is C1-C4 alkyl (especially t-butyl);
- R1 is H or C1-C4 alkyl;
- R2 is Me, Et, n-Pr, i-Pr, or (S) sec-butyl;
- R3 is Me, Et, or n-Pr;
- X1 is Cl, Br, I, triflate, mesylate, or tosylate;
- X2 is C1-C3 alkyl, aryl or benzyl;
- the aryl or benzyl group being optionally substituted with Cl, Br, Me, Et, CN, NO2 or O(C1-C3 alkyl);
- PG is a silyl protective group;
- and
- LG is a leaving group.
Dependencies are inferred from the claim text.