Cenacitinib

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Cenacitinib

CAS 2641636-52-2

MF C19H19F2N7O3 MW431.4

Urea, N-[(1R,2S)-2-fluorocyclopropyl]-N′-[5-[(7-fluoro-2,3-dihydro-1,4-benzodioxin-5-yl)amino]-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl]-

N-{5-[(7-fluoro-2,3-dihydro-1,4-benzodioxin-5-yl)amino]-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl}-N′-[(1R,2S)-2-fluorocyclopropyl]urea

Janus kinase inhibitor, anti-inflammatory, VTX958, VTX 958, SB88R8KGL3

VTX958 for the Treatment of Moderately to Severely Active Crohn’s Disease

CTID: NCT05688852

Phase: Phase 2

Status: Terminated

Date: 2025-07-03

SYN

[US20210139486]

https://patentscope.wipo.int/search/en/detail.jsf?docId=US323750705&_cid=P22-MKEUDK-45432-1

Example 4: Synthesis of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (5)

Step 1: To a solution of 1E (100 g, 288 mmol) and 2E (57 g, 345 mmol) in dry 1,4-dioxane (3000 mL) under N ₂atmosphere was added Cs ₂CO ₃(141 g, 432 mmol), Pd(OAc) ₂(5.2 g, 23.3 mmol) and BINAP (28.6 g, 46.6 mmol). After stirring at 115° C. overnight, the reaction mixture was cooled to rt. and diluted with hexane (3000 mL). The solid was collected by filtration and washed with 2×1500 mL (50% hexane in DCM). The solid was suspended into 5000 mL water and stirred for 1 h. The solid was collected by filtration and dried under vacuum to afford compound 2 (90 g, 65%) as a brown solid.

Step 2: To a solution of compound 2 (70 g, 145 mmol) in NMP (2000 mL) was added saturated NH ₄Cl (aq., 1000 mL) and Fe (92.8 g, 1.45 mol). After stirring at 80° C. for 5.0 hours, the reaction mixture was cooled to rt. and filtrated. The filtrate was poured into water (20 L) and the solid was collected by filtration. The solid was dissolved with DCM (˜1500 mL) and flashed through a short silica gel column, the column was washed with another 3000 mL of DCM/MeOH=30/1. The organic phases were concentrated under vacuum. The residue was triturated by EtOH/MeCN (2000 mL, 5/1, v/v). The solid was collected by filtration and dried under vacuum to afford compound 3 (46 g, 71%) as a brown solid.

Step 3: To a solution of compound 3 (86 g, 0.19 mol, 1.0 eq.) in DMF (800 mL) was added 3C (44.7 g, 0.23 mol, 1.3 eq.) and TEA (38.6 g, 0.38 mol, 2 eq.). After stirring at 80° C. for 2 hours, the reaction mixture was cooled to RT and poured into water (8000 mL). The solid was collected by filtration and dried under vacuum. The residue was triturated by EtOH/MeCN (1200 mL, 5/1, v/v). The solid was collected by filtration and dried under vacuum to afford compound 4 (75 g, 71%) as a brown solid.

Step 4: To a solution of compound 4 (118 g, 0.21 mol, 1.0 eq.) in DCM (1200 mL) was added triethylsilane (37.3 g, 0.32 mol, 1.5 eq.). After stirring for 10 mins, TFA (240 mL) was added into the mixture and the reaction solution was stirred at rt. for 0.5 hour. TfOH (60 mL) was added and the reaction solution was stirred at rt. for another 2 hour. The reaction mixture was poured into saturated NaHCO ₃(30 mL). The solid was collected by filtration and dried under vacuum. The solid was triturated with EtOH (500 mL) and collected by filtration. The solid was triturated with EtOAc (2×500 mL). The solid was collected by filtration and dried under vacuum to afford 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (5) (80 g, 86%) as a yellow solid. LCMS: 432.1 [M+H] ⁺.

PAT

Tyk2 pseudokinase ligands

Publication Number: US-2021139486-A1

Priority Date: 2019-11-08