Process and intermediates for making tubulysin analogs

Patent metadata

Field	Value
Publication number	US-10106560-B2
Application number	US-201715623570-A
Country	US
Kind code	B2
Filing date	Jun 15, 2017
Priority date	Jun 16, 2016
Publication date	Oct 23, 2018
Grant date	Oct 23, 2018

Abstract

An improved process for making a compound B of the structure

wherein n, R 1 , R 2 , and R 3 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.

First claim

What is claimed is:

1. 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
R 3 —X 1   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
R 0 is C 1 -C 4 alkyl;
R 3 is Me, Et, or n-Pr;
X 1 is Cl, Br, I triflate, mesylate, or tosylate; and
PG is a silyl protective group.

2. A process according to claim 1 , wherein
R 3 is n-Pr, X 1 is Br,
the de-chelating agent is DMF, and
PG is triisopropyl silyl.

3. A process according to claim 2 , wherein compound 18 has a structure represented by formula 18a:

4. 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;
R 1 is H or C 1 -C 4 alkyl;
R 2 is Me, Et, n-Pr, i-Pr, or (S) sec-butyl;
R 3 is Me, Et, or n-Pr;
PG is a silyl protective group; and
LG is a leaving group.

5. A process according to claim 4 , wherein
the haloalkyl aluminum compound is Al(X 4 ) 2 R 4 or Al(R 4 ) 2 X 4 , where R 4 is methyl, ethyl, or isobutyl, and
X 4 is Cl or Br.

6. A process according to claim 4 , wherein the haloalkyl aluminum compound is Et 2 AlCl.

7. A process according to claim 6 , wherein
n is 1;
R 1 is Me;
R 2 is (S) sec-butyl;
R 3 is n-Pr;
PG is triisopropyl silyl; and
LG is pentafluorophenoxy.

8. 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;
R 1 is H or C 1 -C 4 alkyl;
R 2 is Me, Et, n-Pr, i-Pr, or (S) sec-butyl;
R 3 is Me, Et, or n-Pr; and
X 2 is C 1 -C 3 alkyl, aryl or benzyl; the aryl or benzyl group being optionally substituted with Cl, Br, Me, Et, CN, NO 2 or O(C 1 -C 3 alkyl).

9. A method according to claim 8 , comprising the steps of
(a) treating compound 25 with a silicon or boron metalating agent in the presence of a metal catalyst selected from the group consisting of a Pd, Pt, Cu, Ru, Rh and Au catalyst, to produce a metalated intermediate; and
(b) oxidizing the metalated intermediate with an oxidizing agent to produce compound 26.

10. A process according to claim 9 , wherein
the metal catalyst is tris(dibenzylideneacetone)dipalladium(0),
the metalating agent is (EtO) 2 SiMeH, and
the oxidizing agent is hydrogen peroxide.

11. A process according to claim 10 , wherein
n is 1,
R 1 is Me,
R 2 is (S) sec-butyl,
R 3 is n-Pr, and
X 2 is C 1 -C 3 alkyl.

12. 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;
R 1 is H or C 1 -C 4 alkyl;
R 2 is Me, Et, n-Pr, i-Pr, or (S) sec-butyl;
R 3 is Me, Et, or n-Pr; and
X 2 is C 1 -C 3 alkyl, aryl or benzyl; the aryl or benzyl group being optionally substituted with Cl, Br, Me, Et, CN, NO 2 or O(C 1 -C 3 alkyl).

13. A process according to claim 12 , wherein the asymmetric hydrogenation catalyst is an R,R-Noyori catalyst.

14. A process according to claim 13 , wherein the R,R-Noyori catalyst has the structure

15. A process according to claim 14 , wherein
n is 1,
R 1 is Me,
R 2 is (S) sec-butyl,
R 3 is n-Pr, and
X 2 is C 1 -C 3 alkyl.

16. 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;
R 0 is C 1 -C 4 alkyl (especially t-butyl);
R 1 is H or C 1 -C 4 alkyl;
R 2 is Me, Et, n-Pr, i-Pr, or (S) sec-butyl;
R 3 is Me, Et, or n-Pr;
X 1 is Cl, Br, I, triflate, mesylate, or tosylate;
X 2 is C 1 -C 3 alkyl, aryl or benzyl; the aryl or benzyl group being optionally substituted with Cl, Br, Me, Et, CN, NO 2 or O(C 1 -C 3 alkyl);
PG is a silyl protective group; and
LG is a leaving group.

Assignees

• Bristol Myers Squibb Co

Inventors

• Ortiz Adrian
• Guerrero Carlos A
• Zheng Bin
• Zhu Jason J
• Schmidt Michael Anthony
• Luzung Michael R
• Eastgate Martin D

Classifications

• C07F7/1852

  Chemistry & Metallurgy · mapped topic

• C07F7/0818

  Chemistry & Metallurgy · mapped topic

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D211/28 Primary

  to which a second hetero atom is attached · CPC title

• C07F7/1856 Primary

  Chemistry & Metallurgy · mapped topic