Civorebrutinib

WS-413, 933NK55FMX

5-amino-3-[4-(5-chloropyridin-2-yl)oxyphenyl]-1-[(6R)-4-cyano-4-azaspiro[2.5]octan-6-yl]pyrazole-4-carboxamide

Civorebrutinib (WS-413) is a Bruton’s tyrosine kinase inhibitor with antineoplastic effect.

Scheme

Patent

Zhejiang Yukon Pharma Co., Ltd. WO2017198050

WO2019091440

WO2019091438

PATENT

WO2019091441

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019091441&_cid=P10-MADPL7-76599-1

Example 1 

[0116]Preparation of (R)-5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1-(4-cyano-4-azaspiro[2.5]octan-6-yl)-1H-pyrazole-4-carboxamide (Compound 1)

Step 1 

[0119]

[0120]DIPEA (185 g, 1.44 mol, 250 mL, 3 eq) was added to a solution of intermediate compound 11 (167 g, 479 mmol, 1 eq) in EtOH (1670 mL) at 0 ° C. Intermediate compound 17 (187 g, 575 mmol, 1.2 eq) was added to the mixture. The mixture was then stirred at 25 ° C for 12 h under a N2 atmosphere. LCMS (ET14245-55-P1A2, product: RT = 1.723 min) showed that the reaction was complete. The reaction was filtered to obtain the product. The product was used directly in the next step without purification. Intermediate compound 18 (243 g, 407 mmol, yield 85%, purity 93.1%) was obtained as a white solid. 

[0121]Step 2 

[0122]

[0123]Intermediate compound 18 (121 g, 218 mmol, 1 eq) was stirred in H 

₂ SO 

₄ (1200 mL) at 30° C. for 36 h. TLC (DCM: MeOH=10:1, Rf=0.9) showed that compound 18 was completely consumed and only one desired spot was formed (DCM: MeOH=10:1, Rf=0.2). Multiple batches of reaction mixtures were combined, and the combined mixture was poured into MTBE (20 L), solids were precipitated and the filtrate was collected by suction filtration. The pH of the filtrate was adjusted to 10 with aqueous ammonia, extracted with EtOAc (2 L x 10), dried with Na 

₂ SO 

₄ , filtered and concentrated under reduced pressure to give intermediate compound 19 (crude product 311 g, equivalent to 238 g product) as a yellow solid. 

[0124]Step 3 

[0125]

[0126]To a solution of intermediate compound 19 (199 g, 453 mmol, 1 eq) in DMF (1400 mL) was added cesium carbonate (295 g, 907 mmol, 2 eq) and stirred at 15 ° C for 0.5 hours. Then BrCN (52.8 g, 499 mmol, 36.7 mL, 1.1 eq) was added and stirred at 15 ° C for 2 hours. TLC (DCM: MeOH = 10: 1, R 

_f = 0.2) showed that compound 19 was completely reacted and only one desired spot was generated (DCM: MeOH = 10: 1, R 

_f = 0.6). Multiple batches of reaction mixtures were combined and the resulting mixture was filtered to remove cesium carbonate. The filtrate was then concentrated under reduced pressure to remove DMF. The residue was diluted with water (2 L) and extracted with ethyl acetate (1 L × 4). The organic phases were combined and washed with water (2 L × 2) and brine (2 L), dried over sodium sulfate, filtered and concentrated under reduced pressure. Acetonitrile (1 L) was added to the residue to precipitate a white solid, which was filtered and the filter cake was washed with acetonitrile (200 mL×2) to give Compound 1 (140 g, 302 mmol, yield 55%, purity 97.0%). 

[0127]

¹H NMR：CDCl ₃400MHzδ8.05(d，J＝2.4Hz，1H)，7.60(dd，J＝2.4，8.8Hz，1H)，7.51(d，J＝8.8Hz，2H)，7.15(d，J＝8.8Hz，2H)，6.86(d，J＝8.8Hz，1H)，5.60(s，2H)，5.23(br.s.，2H)，4.22-4.16(m，1H)，3.59-3.41(m，2H)，2.39-2.24(m，2H)，2.12-2.09(m，1H)，1.23-1.10(m，2H)，0.80-0.74(m，2H)，0.62-0.61(m，1H).

[1]. Wu Y, et al. 5-Aminopyrazole carboxamide derivative as BTK inhibitor and its preparation. World Intellectual Property Organization, WO2017198050 A1 2017-11-23.

////////Civorebrutinib, WS-413, WS 413, 933NK55FMX