Novel Process for Making Compounds for Use in the Treatment of Cancer
AssigneesExelixis, Inc., Genentech, Inc.
InventorsSriram Naganathan, Nathan Guz, Matthew Pfeiffer, C. Gregory Sowell, Tracy Bostick, Jason Yang, Amit Srivastava, Neel Kumar Anand
Life of this patent
Estimating the term…
Abstract
Disclosed herein is a process of making a compound of formula I The compound of formula I is an inhibitor of MEK and thus can be used to treat cancer.
Claims48
A process for making a compound of formula I:
- wherein:
- A is arylene or heteroarylene optionally substituted with one, two, three, or four groups selected from R6, R7, R8, and R9, each of which are independently selected from hydrogen, halo, (C1-C8)alkyl, halo(C1-C8)alkyl, hydroxy, (C1-C6)alkoxy, and halo(C1-C6)alkoxy;
- X is alkyl, halo, halo(C1-C8)alkyl, or halo(C1-C6)alkoxy;
- R1, R2, R3, and R4 are each independently hydrogen, (C1-C8)alkyl, or halo(C1-C8)alkyl;
- R5 is hydrogen, halo, or (C1-C8)alkyl;
- comprising:
- contacting a compound of formula II-1 wherein X and R5 are as defined above with a compound of formula IIa-1 wherein R10 is F, Br, Cl, or —OSO2—CF3 and R11 is H or a protecting group to provide a compound of formula I.
A process for preparing a compound of formula I′, comprising contacting a compound of formula IIa with a compound of formula II.
A process for preparing a compound of formula II, comprising deprotecting a compound of formula III.
A process for preparing a compound of formula II, comprising contacting a compound of formula IVa with a compound of formula IV.
A process for preparing a compound of formula IV, comprising deprotecting a compound of formula V:
- wherein PG is an amino protecting group.
A process for preparing a compound of formula V wherein PG is an amino protecting group, comprising reducing a compound of formula VI.
A process for preparing a compound of formula VI comprising reacting a compound of formula VII with a compound of formula VIIa in the presence of base:
- wherein PG is an amino protecting group.
A process for preparing a compound of formula V, comprising:
- 1) reacting a compound of formula VII with a compound of formula VIIa to provide a compound of formula VI;
- and
- 2) reducing a compound of formula VI with a reducing agent selected from the group consisting of borohydrides to provide a compound of formula V.
A process for the preparation of the compound of formula IV, comprising:
- 1) reacting a compound of formula VII with a compound of formula VIIa to provide a compound of formula VI;
- 2) reducing a compound of formula VI with a reducing agent selected from the group consisting of borohydrides to provide a compound of formula V;
- and
- 3) deprotecting the azetidinyl ring of a compound of formula V to provide a compound of formula IV.
A process for the preparation of the compound of formula III, comprising:
- 1) reacting a compound of formula VII with a compound of formula VIIa to provide a compound of formula VI;
- 2) reducing a compound of formula VI with a reducing agent selected from the group consisting of borohydrides to provide a compound of formula V;
- 3) deprotecting the azetidinyl ring of a compound of formula V to provide a compound of formula IV;
- and
- 4) reacting a compound of formula IV with a compound of formula IVa to provide a compound of formula III.
A process for the preparation of the compound of formula II, comprising:
- 1) reacting a compound of formula VII with a compound of formula VIIa to provide a compound of formula VI;
- 2) reducing a compound of formula VI with a reducing agent selected from the group consisting of borohydrides to provide a compound of formula V;
- 3) deprotecting the azetidinyl ring of a compound of formula V to provide a compound of formula IV;
- 4) reacting a compound of formula IV with a compound of formula IVa to provide a compound of formula IIII;
- and
- 5) hydrogenation of a compound of formula III to provide a compound of formula II.
A process for the preparation of the compound of formula I′, comprising:
- 1) reacting a compound of formula VII with a compound of formula VIIa to provide a compound of formula VI;
- 2) reducing a compound of formula VI with a reducing agent selected from the group consisting of borohydrides to provide a compound of formula V;
- 3) deprotecting the azetidinyl ring of a compound of formula V to provide a compound of formula IV;
- 4) reacting a compound of formula IV with a compound of formula IVa to provide a compound of formula III;
- 5) hydrogenation of a compound of formula III to provide a compound of formula II;
- and
- 6) reacting a compound of formula II with a compound of formula IIa to provide a compound of formula I′.
A process for the preparation of the compound of formula I′, comprising:
- a) hydrogenation of a compound of formula III to provide a compound of formula II;
- and
- b) reacting a compound of formula II with a compound of formula II, to provide a compound of formula I′.
A process for the preparation of the compound of formula I′, comprising:
- a) reacting a compound of formula IV with a compound of formula IVa to provide a compound of formula III;
- b) hydrogenation of a compound of formula III to provide a compound of formula II;
- and
- c) reacting a compound of formula II with a compound of formula IIa to provide a compound of formula I′.
A process for the preparation of the compound of formula I′, comprising:
- a) deprotecting the azetidinyl ring of a compound of formula V to provide a compound of formula IV;
- b) reacting a compound of formula IV with a compound of formula IVa to provide a compound of formula III;
- c) hydrogenation of a compound of formula III to provide a compound of formula II;
- and
- d) reacting a compound of formula II with a compound of formula IIa to provide a compound of formula I′.
A process for the preparation of the compound of formula I′, comprising:
- a) reducing a compound of formula VI with a reducing agent selected from the group consisting of borohydrides to provide a compound of formula V;
- b) deprotecting the azetidinyl ring of a compound of formula V to provide a compound of formula IV
- c) reacting a compound of formula IV with a compound of formula IVa to provide a compound of formula III;
- d) hydrogenation of a compound of formula III to provide a compound of formula II;
- and
- e) reacting a compound of formula II with a compound of formula IIa to provide a compound of formula I′.
A compound which is:
- wherein PG is a protecting group;
- wherein PG is an amino protecting group;
A compound of formula IV
A compound of formula III.
A compound of formula II.
Dependencies are inferred from the claim text.