RU-2861342-C2 - SYNTHESIS OF BISMESYLATE SALT OF 4-AMINO-N-(1-((3-CHLORO-2-FLUOROPHENYL)AMINO)-6-METHYLISOQUINOLIN-5-YL)THIENO[3,2-D]PYRIMIDINE-7-CARBOXAMIDE AND INTERMEDIATE COMPOUNDS THEREOF

Abstract

FIELD: organic chemistry. SUBSTANCE: invention relates to a method for the synthesis of the bismesylate salt of formula 1b, including some intermediate compounds thereof. 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide is used as a MAPK inhibitor for treating tumours. Proposed method comprises reacting compound 4 with compound 5a to obtain compound 6a, reducing compound 6a with hydrogen on a platinum and vanadium based catalyst in an aqueous ammonia solution in 2-methyltetrahydrofuran to form a compound of formula 7, coupling compound 7 with compound 2 in the presence of N,N,N,N-tetramethylchloroformamidinium hexafluorophosphate and 2,6-lutidine in THF to obtain adduct 1 (THF), and dissolving 1 (THF) in an aqueous MsOH mixture in isopropyl alcohol to obtain the pure form 1b. EFFECT: method provides the compound 1b with good yield, purity and salt stability. 11 cl, 11 dwg, 2 tbl, 19 ex

Inventors

• GOSSELIN FRANCIS
• GE YONGHUI
• ZHANG JIE
• BIGLER RAPHAEL
• FINET LAURE ELISABETH SIMONE
• MONDIERE REGIS JEAN GEORGES
• NAKAGAWA YUKI
• KOENIG STEFAN G.
• MERCADO-MARIN Eduardo V.
• STUMPF ANDREAS
• ZELL DANIEL
• ZHANG HAIMING
• BACHMANN STEPHAN
• CARRERA DIANE ELIZABETH
• DALZIEL MICHAEL EUAN

Dates

Publication Date

20260505

Application Date

20220628

Priority Date

20210630

Claims (20)

1. 1. Method for synthesizing a compound of formula 1b
2. wherein the method includes:
3. reacting compound 4 with compound 5a to give compound 6a
4. reduction of compound 6a with hydrogen on a platinum-vanadium catalyst, with an aqueous solution of ammonia, in 2-methyltetrahydrofuran as a solvent to form compound 7
5. coupling of compound 7 with compound 2 using N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and 2,6-lutidine in THF to give the adduct of THF and 1
6. dissolution of 1 (THF) with an aqueous mixture of methanesulfonic acid (MsOH) in isopropyl alcohol to obtain pure form 1b.
7. 2. The method according to claim 1, wherein the purity of Ib is >99 A% by HPLC.
8. 3. The method according to claim 1, wherein compound 2 is obtained by a process comprising:
9. regioselective bromination of 22 to give 23
10. chlorination of 23 to form 24
11. converting 24 into a secure connection 25
12. carbonylation of 25 to form 26
13. deprotection of 26 with acid, then base, followed by neutralization with acetic acid to yield compound 2.
14. 4. The method according to claim 1, wherein compound 4 is obtained by a process comprising:
15. selective methylation of 5-nitroisoquinoline to give 42
16. oxidation of 42 to yield 43
17. chlorination of 43 to yield 4.
18. 5. The method according to claim 1, wherein compound 5a is obtained by a process comprising:
19. regioselective fluorination of 50 to give 51
20. catalytic reduction of 51 with H 2 on Raney nickel to give 5a,

Description

AREA OF TECHNOLOGY [0001] The procedure described herein generally relates to the synthesis, crystallization, and purification of the bis-mesylate salt of 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide. The procedure more particularly relates to the synthesis and preparation on an industrial scale, including certain intermediates. LEVEL OF TECHNOLOGY [0002] 4-Amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (1) is a potent inhibitor of the mitogen-activated protein kinase (MAPK) pathway that has shown selective activity against advanced solid tumors that carry various RAS and RAF mutations (see, e.g., U.S. Patent No. 9,156,852), and in various salt forms is currently undergoing clinical trials for several therapeutic indications. [0003] The MAPK pathway plays an important role in the control of cell growth and proliferation, and a number of different defects in this signaling cascade are now understood to be the most significant causes of many human cancers. (See, e.g., Solit, D.B. et al., BRAF mutation predicts sensitivity to MEK inhibition, Nature 439, 358–362 (2006)). The RAF family of serine/threonine protein kinases is an important component of the MAPK pathway, and certain mutations in its A-, B-, or C-RAF members lead to dysregulation of signal transducers that have been identified as a common cause of human cancer {e.g., Yen, L., Shanahan, F., Lee, J. et al., Nature 594, 418–423 (2021)). In recent years, significant progress has been made in selectively inhibiting mutated RAF kinases (e.g., Huestis, M.P., et al., J. Med. Chem. 2021, 64, 3940–3955; and Huestis, M.P., et al., ACS Med. Chem. Lett. (2021), DOI: 10.1021/acsmedchemlett.1c00063), although molecules that act as inhibitors of all three RAF members (so-called “pan-RAF inhibitors”), such as 1, have also become important. [0004] To date, 1 has been provided to patients in clinical studies as the bis-HCl (bis-hydrochloride) salt 1a, manufactured to scale according to the scheme in Fig. 1. However, both the bis-HCl salt and its previous method of preparation have significant drawbacks. [0005] The method shown in Fig. 1 began with a nucleophilic aromatic substitution reaction (S N Ar) between 1-chloro-6-methyl-5-nitroisoquinoline 4 and 3-chloro-2-fluoroaniline 5 to give the intermediate, HCl salt 6a. The nitro group of the organic moiety 6a was then reduced to give the isoquinoline intermediate 7 (Fig. 1). The latter was then introduced into an amide coupling with thienopyrimidone 3 to give the penultimate intermediate 8. In this method, the pyrimidone moiety 3 was converted in a one-pot procedure to the chloropyrimidine moiety in 8 using POCl 3 as both the acid activator and the chlorinating reagent. In the final step, 8 was aminated to yield the crude bis-hydrochloride salt 1a, which required extensive purification using a multi-step resuspension protocol. [0006] The scheme of Figure 1 has a number of significant limitations, including: a) the potential formation of impurities in several steps of the process, any of which would be problematic if present in trace amounts in the pharmaceutical finished product; b) the use of super-stoichiometric amounts of zinc to reduce the nitro group of 6a, which is both expensive and requires additional purification to remove excess metal; c) the need for multiple reslurry purifications to remove impurities from the amide coupling product that produced intermediate 8, resulting in solvent waste as well as a general lack of efficiency; d) the susceptibility of the chloropyrimidine intermediate 8 to hydrolysis, which replaces the chloro-containing group with hydroxyl in the next step; e) the significant volume of waste products generated, such as excess zinc, arising from the reduction of 6a; and (e) the lack of a reliable crystallization process to ensure sufficient formation and impurity control of the bis-hydrochloride salt 1a, meaning that purification was very time-consuming. [0007] Another scheme relative to that in Fig. 1 (see WO 2013/100632) has been presented, which uses 4-aminothieno[3,2-d]pyrimidine-7-carboxylic acid instead of thienopyrimidine 3, which also has the disadvantages associated with the formation of the bis-HCl salt. [0008] In particular, the use and preparation of the bis-hydrochloride salt form of 1a was associated with several practical difficulties. First, it was very difficult to control the stoichiometry of hydrochloric acid at elevated temperatures due to evaporation, meaning that the finished product often contained a hydrolysis impurity (arising from the hydrolysis of the amino group of 1). This problem could not be directly addressed by using excess HCl due to hydrolysis and because product 1a itself could still undergo disproportionation upon handling (for mixing the free base of 1 and its mono-HCl and di-HCl salts). Second, there are safety concerns associate