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-11999749-B2
Application number	US-202217852227-A
Country	US
Kind code	B2
Filing date	Jun 28, 2022
Priority date	Jun 30, 2021
Publication date	Jun 4, 2024
Grant date	Jun 4, 2024

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.

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 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.

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

3. 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.

4. 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.

5. 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 H 2 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.

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 compound 7 takes place via intermediate 6

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 POCl 3 and Et 3 N;

aminating compound 24 with t-BuNH 2 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 Et 3 N;

and
deprotecting compound 26 with sulfuric acid followed by potassium hydroxide to form compound 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 and TCFH in THF, followed by washing with acetone.

10. A compound of formula:

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.

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.

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

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