# US 2020/0392104 A1 · Novel Process for Making Compounds for Use in the Treatment of Cancer

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- Number: US 2020/0392104 A1
- Document ID: US20200392104A1
- Status: Published application
- Kind: A1
- Application number: 17/003,570
- Filed: 2020-08-26
- Published: 2020-12-17
- Earliest claimed: 2012-10-12
- Assignees: Exelixis, Inc.; Genentech, Inc.
- Applicants: Exelixis, Inc.; Genentech, Inc.
- Inventors: Sriram Naganathan; Nathan Guz; Matthew Pfeiffer; C. Gregory Sowell; Tracy Bostick; Jason Yang; Amit Srivastava; Neel Kumar Anand
- Web page: https://patentgrep.com/patent/US20200392104A1

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 498/04: Ortho-condensed systems
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The process of any one of claim 1, wherein X and R5 in a compound of formula IIa-1 are each independently F, Cl, Br, or I.

### Claim 3 (depends on 1, 2)

The process of any one of claims 1 or 2, wherein X is F and R5 is I.

### Claim 4 (depends on 1, 2, 3)

The process of any one of claims 1 to 3 wherein the compound of formula II-1 is the compound of formula II-2:
wherein R11 is H or a protecting group and Ring A is optionally substituted with one, two, three or four groups selected from R6, R7, R8, and R9, each of which are independently selected from halo, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C6)alkoxy, and halo(C1-C6)alkoxy.

### Claim 5 (depends on 1, 2, 3, 4)

The process of any one of claims 1 to 4, wherein Ring A in the compound of formula II-2 is phenyl or pyridyl.

### Claim 6 (depends on 1, 2, 3, 4, 5)

The process of any one of claims 1 to 5, wherein the compound of formula II-1 is the compound of formula II-3:
wherein R11 is as defined previously and R10 is F, Cl, Br, I, or OSO2CF3, and R12a and R12b are each independently F, Cl, Br, I, alkyl, haloalkyl, alkoxy, or haloalkoxy.

### Claim 7 (depends on 6)

The process of claim 6, wherein R10 in the compound of formula II-3 is F, Cl, Br, or I, and R12a and R12b are each independently F, Cl, Br, alkyl, haloalkyl, alkoxy, or haloalkoxy.

### Claim 8 (depends on 1, 2, 3, 4, 5, 6)

The process of any one of claims 1 to 6, wherein R10 in the compound of formula II-3 is F and R12a and R12b are each independently F, Cl, alkyl, or alkoxy.

### Claim 9

A process for preparing a compound of formula I′, comprising contacting a compound of formula IIa with a compound of formula II.

### Claim 10 (depends on 9)

The process of claim 9, further comprising a strong base.

### Claim 11 (depends on 10)

The process of claim 10, wherein the strong base is selected from the group consisting of butyllithium, t-butyllithium, the lithium, sodium, or potassium salts of mono or bis substituted alkyl or aromatic amines, and silylalkyl or silylaromatic amines.

### Claim 12 (depends on 10, 11)

The process of any one of claims 10 or 11, wherein the strong base is selected from the group consisting of the lithium, sodium, or potassium salts of diisopropyl amine, bis(trimethylsilyl)amine, diethylamine, and dimethylamine.

### Claim 13 (depends on 10, 11, 12)

The process of any one of claims 10 to 12, wherein the strong base is selected from the group consisting of preferably the lithium, sodium, or potassium salts of bis(trimethylsilyl)amine.

### Claim 14 (depends on 10, 11, 12, 13)

The process of any one of claims 10 to 13, wherein the strong base is selected from the group consisting of lithium diisopropylamide, lithium bis(trimethylsilyl)amide, or lithium diethylamide.

### Claim 15 (depends on 10, 11, 12, 13, 14)

The process of any one of claims 10 to 14, wherein the strong base is lithium bis(trimethylsilyl)amide.

### Claim 16 (depends on 10, 11, 12, 13, 14, 15)

The process of any one of claims 10 to 15, wherein reaction is performed in the presence of a solvent which is tetrahydrofuran.

### Claim 17

A process for preparing a compound of formula II, comprising deprotecting a compound of formula III.

### Claim 18 (depends on 17)

The process of claim 17, wherein deprotection comprises hydrogenation using H2 in the presence of a heterogeneous transition metal hydrogenation catalyst or treatment with chloroethyl chloroformate in the presence of MeCN or Na/NH3.

### Claim 19 (depends on 18)

The process of claim 18, wherein the heterogeneous transition metal hydrogenation catalyst is selected from the group consisting of a Raney catalyst, Pd/C, Pd(OH)2/C, Pd(OAc)2, Au/TiO2, Rh/C, Ru/Al2O3, Ir/CaCO3, Pt/C, and Palladium(0) microencapsulated in polyurea matrix as a 45 percent mixture of nanoparticles of palladium approximately 2 nm in size in water, containing 0.4 mmol/g Pd(0) (dry basis), where the unit weight includes the weight of water (NP Pd(0) Encat™ 30), or a mixture thereof.

### Claim 20 (depends on 18)

The process of claim 18 in the presence of HCl and acetic acid.

### Claim 21 (depends on 17, 18, 19, 20)

The process of claims 17 to 20, wherein the heterogeneous transition metal hydrogenation catalyst is Pd/C.

### Claim 22

A process for preparing a compound of formula II, comprising contacting a compound of formula IVa with a compound of formula IV.

### Claim 23 (depends on 22)

The process of claim 22 in the presence of an inorganic base.

### Claim 24 (depends on 22)

The process of claim 22, wherein the inorganic base is an alkali or alkali earth metal hydroxide, phosphate, or carbonate.

### Claim 25 (depends on 22, 23, 24)

The process of any one of claims claim 22 to 24, wherein the inorganic base is selected from the group consisting LiOH, NaOH, KOH, CsOH, NH4OH, RbOH, Mg(OH)2, Ca(OH)2, Ba(OH)2, Li2CO3, Na2CO3, K2CO3, Cs2CO3, (NH4)2CO3, and K3PO4.

### Claim 26 (depends on 22, 23, 24, 25)

The process of any one of claims 22 to 25, wherein the inorganic base is K3PO4, K2CO3, or KOH.

### Claim 27

A process for preparing a compound of formula IV, comprising deprotecting a compound of formula V:
wherein PG is an amino protecting group.

### Claim 28 (depends on 27)

The process of claim 27, wherein the protecting group is an FMoc, CBz, or BOC protecting group.

### Claim 29 (depends on 26, 27, 28)

The process of any one of claims 26 to 28, wherein the protecting group is a BOC protecting group.

### Claim 30

A process for preparing a compound of formula V wherein PG is an amino protecting group, comprising reducing a compound of formula VI.

### Claim 31 (depends on 30)

A process according to claim 30, in the presence of a reducing agent, in particular wherein the reducing agent is selected from the group consisting of borohydrides.

### Claim 32

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.

### Claim 33

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.

### Claim 34

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.

### Claim 35

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.

### Claim 36

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.

### Claim 37

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′.

### Claim 38

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′.

### Claim 39

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′.

### Claim 40

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′.

### Claim 41

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′.

### Claim 42

A compound which is:
wherein PG is a protecting group;
wherein PG is an amino protecting group;

### Claim 43 (depends on 42)

The compound of claim 42 which is a compound of formula V:
wherein PG is an amino protecting group.

### Claim 44 (depends on 37)

The compound of claim 37 which is a compound of formula VI:
wherein PG is an amino protecting group.

### Claim 45 (depends on 43, 44)

The compounds of claims 43 or 44, wherein the amino protecting group is BOC.

### Claim 46

A compound of formula IV

### Claim 47

A compound of formula III.

### Claim 48

A compound of formula II.