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

Patent metadata

Field	Value
Publication number	US-2023028651-A1
Application number	US-202217852227-A
Country	US
Kind code	A1
Filing date	Jun 28, 2022
Priority date	Jun 30, 2021
Publication date	Jan 26, 2023
Grant date	—

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 PtN/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.

First claim

What is claimed:

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 an adduct of THF and 1; and

dissolving 1 (THF) with an aqueous mixture of methanesulfonic acid (MsOH) in iso-propyl alcohol, to provide a pure form of 1b.

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

3 . The method of claim 1 , wherein compound 2 is prepared by a process comprising:
regioselective bromination of 22 to produce 23;

chlorinating 23 to form 24;

converting 24 to a protected compound 25;

carbonylation of 25 to form 26;

and
deprotecting 26 with acid, then base, followed by neutralization with acetic acid to provide compound 2.

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

oxidizing 42 to produce 43;

and
chlorinating 43 to produce 4.

5 . The method of claim 1 wherein compound 5a is prepared by a process comprising:
regioselectively fluorinating 50 to produce 51;

and
catalytically reducing 51 with H 2 over Raney-nickel to produce 5a,
wherein the fluorinating and reducing occur in the same reaction vessel without separating compound 51 between each step.

6 . 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 NEt 3 .

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

8 . A method of synthesizing a compound of formula 2, the method comprising:

reacting 20 with 21 in methoxyethanol to produce 22;

brominating 22 with dibromine in a sodium acetate buffer to give 23;

converting 23 to 24 by reaction with POCl 3 and Et 3 N;

aminating 24 with t-BuNH 2 to produce 25;

converting 25 to 26 by reaction with (R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene in the presence of Pd(OAc) 2 in Et 3 N;

and
deprotecting 26 with sulfuric acid followed by potassium hydroxide to form 2.

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, TCFH in THF, followed by washing with acetone.

10 . A compound of formula:

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

Assignees

• Genentech Inc
• Hoffmann La Roche

Inventors

• Gosselin Francis
• Koenig Stefan G
• Mercado-Marin Eduardo V
• Stumpf Andreas
• Zell Daniel
• Zhang Haiming
• Bachmann Stephan
• Carrera Diane E
• Dalziel Michael E
• Ge Yonghui
• Zhang Jie
• Bigler Raphael
• Finet Laure Elizabeth Simone
• Mondiere Regis Jean Georges
• Nakagawa Yuki

Classifications

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title