# US 11,999,749 B2 · Synthesis of a bis-mesylate salt of 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide and intermediates thereto

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- Number: US 11,999,749 B2
- Document ID: US11999749B2
- Status: Granted
- Kind: B2
- Application number: 17/852,227
- Filed: 2022-06-28
- Published: 2023-01-26
- Granted: 2024-06-04
- Earliest claimed: 2021-06-30
- Assignees: Genentech, Inc.; Hoffmann-La Roche Inc.
- Applicants: Genentech, Inc.; Hoffmann-La Roche Inc.
- Inventors: Francis Gosselin; Stefan G. Koenig; Eduardo V. Mercado-Marin; Andreas Stumpf; Daniel Zell; Haiming Zhang; Stephan Bachmann; Diane E. Carrera; Michael E. Dalziel; Yonghui Ge; Jie Zhang; Raphael Bigler; Laure Elizabeth Simone Finet; Regis Jean Georges Mondiere; Yuki Nakagawa
- Web page: https://patentgrep.com/patent/US11999749B2

## CPC

- C07D 495/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

A manufacturing process to a bis-mesylate salt 1b of the pan-RAF inhibitor 4-amino-n-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide. The process features a number of efficient key reactions, including a robust and scalable Pd-catalyzed carbonylation reaction to generate thienopyrimidine 2 and a highly chemoselective Pt/V/C-catalyzed nitro group reduction to access penultimate intermediate 7. The final amide coupling of 7 and 2 was accomplished by a mild and safe protocol employing N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate (TCFH) as the coupling reagent, to produce a 1:1 adduct of the freebase and THF. The adduct afforded compound 1b with excellent yield, purity, and form stability on a multikilogram production scale after reaction with MsOH and recrystallization. The methods are able to produce a compound having upwards of 95% purity.

## Claims

### Claim 1

A method of synthesizing a compound of formula 1b, the method comprising:
reacting compound 4 with compound 5a to produce compound 6a;
reducing compound 6a with hydrogen over a platinum-vanadium catalyst, with aqueous ammonia, in 2-methyl tetrahydrofuran as a solvent, to form compound 7;
coupling compound 7 with compound 2 using N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate and 2,6-lutidine, in THF, to produce a THF adduct of compound 1; and
dissolving the THF adduct of compound 1 in an aqueous mixture of methanesulfonic acid in iso-propyl alcohol, to provide a pure form of compound 1b.

### Claim 2 (depends on 1)

The method of claim 1 wherein the purity of compound 1b is >99 A % HPLC.

### Claim 3 (depends on 1)

The method of claim 1, wherein compound 2 is prepared by a process comprising:
regioselective bromination of compound 22 to produce compound 23;
chlorinating compound 23 to form compound 24;
converting compound 24 to a protected compound 25;
carbonylation of compound 25 to form compound 26;
and
deprotecting compound 26 with acid, then base, followed by neutralization with acetic acid to provide compound 2.

### Claim 4 (depends on 1)

The method of claim 1 wherein compound 4 is prepared by a process comprising:
selectively methylating 5-nitroisoquinoline to produce compound 42;
oxidizing compound 42 to produce compound 43;
and
chlorinating compound 43 to produce compound 4.

### Claim 5 (depends on 1)

The method of claim 1 wherein compound 5a is prepared by a process comprising:
regioselectively fluorinating compound 50 to produce compound 51;
and
catalytically reducing compound 51 with H2 over Raney-nickel to produce compound 5a, wherein the fluorinating and reducing occur in the same reaction vessel without separating compound 51 between each step.

### Claim 6 (depends on 1)

The method of claim 1, wherein the reacting compound 4 with compound 5a to produce compound 6a, takes place in methyl ethyl ketone, or in MIBK with NEt3.

### Claim 7 (depends on 1)

The method of claim 1, wherein the reducing of compound 6a to form compound 7 takes place via intermediate 6

### Claim 8

A method of synthesizing a compound of formula 2, the method comprising:
reacting compound 20 with compound 21 in methoxyethanol to produce compound 22;
brominating compound 22 with dibromine in a sodium acetate buffer to give compound 23;
converting compound 23 to compound 24 by reaction with POCl3 and Et3N;
aminating compound 24 with t-BuNH2 to produce compound 25;
converting compound 25 to compound 26 by reaction with (R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene in the presence of Pd(OAc)2 in Et3N;
and
deprotecting compound 26 with sulfuric acid followed by potassium hydroxide to form compound 2.

### Claim 9

A method of producing a compound of formula 1 (THF), the method comprising:
coupling a compound of formula 7 with a compound of formula 2,
utilizing 2,6-lutidine and TCFH in THF, followed by washing with acetone.

### Claim 10

A compound of formula:

### Claim 11

A composition comprising a 1:1 adduct of 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide with tetrahydrofuran, or crystalline forms thereof.

### Claim 12

A method of producing a compound of formula 1b, the method comprising:
coupling a compound of formula 7 with a compound of formula 2,
utilizing 2,6-lutidine and TCFH in NMP, followed by
washing the product with dimethyl sulphonic acid, in an aqueous mixture of NMP, thereby isolating the compound of formula 1b.

### Claim 13 (depends on 12)

The method of claim 12, further comprising:
washing the compound of formula 1b in a mixture of DMSO and dimethylsulfonic acid, followed by recrystallization.