Development of a Scalable Negishi Cross-Coupling Process for the Preparation of 2-Chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)aniline

Abstract

A scalable synthesis of 2-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)aniline (1), a key intermediate in the synthesis of an immuno-oncology asset, is described. A Negishi cross-coupling between in situ generated heteroaryl zinc reagent 4 and 5-bromo-2-chloroaniline (3) catalyzed by Pd(Xantphos)Cl 2 enabled the construction of the key aryl−heteroaryl bond. A scalable first-generation process was developed that delivered 1 in multikilogram quantities. Building upon knowledge from the initial process, a more efficient workup and isolation procedure was developed that controlled levels of residual Pd and Zn to consistent levels that were acceptable for downstream processing. The high-yielding optimized process offers streamlined metals remediation, a 30% reduction in the number of unit operations, and a 34% reduction in process mass intensity (PMI) compared to the initial process.

Coupling-Condensation Strategy for the Convergent Synthesis of an Imidazole-Fused 2-Aminoquinoline NLRP3 Agonist

“…The resulting low-potency solids were re-slurried in hot CPME (2.5 vol), cooled to −5 °C, and filtered to yield tert-butyl ((4-cyano-1Himidazol-2-yl)methyl)(ethyl)carbamate (20a, 64 g, 97.5 wt %, 49% yield). mp 168 °C; 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.02 (s, 1H), 4.38 (s, 2H), 2.60 (br s, 2H), 1.35 (m, 9H), 1.10 (t, J = 8.0 Hz, 3H) 13…”

“…The white solids were dried at 50 °C overnight to yield tert-butyl ((4-cyano-5-iodo-1Himidazol-2-yl)methyl)(ethyl)carbamate (22a, 69.0 g, 183 mmol) as a white solid in 91.7% yield. 1 H NMR (500 MHz, DMSO-d 6 ): δ 13.49 (br s, 1H), 4.37 (br s, 2H), 3.22 (br s, 2H), 1.33 (m, 9H), 1.01 (t, J = 6.9 Hz, 3H); 13 N 2 -flushed reactor set to 20 °C was charged with MeOH (8.1 L, 4.5 V), 2-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)aniline 13 (16b, 1.6 kg, 1.2 equiv), potassium pivalate (1.22 kg, 1.8 equiv), and 2-methyl-tetrahydrofuran (6.3 L, 3.5 V), then sparged with N 2 , and agitated for 20 min. To the reactor containing 16b was added tetrahydroxydiboron (792.0 g, 1.8 equiv), and the reaction mixture was sparged with N 2 and agitated for 20 min.…”

“…The cake was dried in a vacuum oven at 50 °C for 15 h. This resulted in 2.12 kg (79.9% yield) of tert-butyl ((4-amino-7-(1H-pyrazol-5-yl)-1H-imidazo [4,5-c] ), 3.41 (q, J = 6.9 Hz, 2H), 1.37 (br s, 9H), 1.12 (t, J = 7.1 Hz, 3H). 13 S2.…”

“…Owing to the broad commercial availability of ZnCl 2 in both the solid form and solution, the Negishi cross-coupling between Ar−ZnCl 13a and 5-bromo-2-chloroaniline (14b) was optimized to give the THP-protected product 16b in 78% isolated yield. 13 Cyanoimidazole Synthesis. Simultaneously, we evaluated the synthesis of the 4-cyano-imidazole fragment as a coupling partner for either a direct arylation or a Suzuki−Miyaura coupling.…”

“…13 C{ 1 H} NMR (176 MHz, DMSO-d 6 , acquired at 75 °C): δ 155.1, 155.0, 148.8, 147.4, 144.9, 144.6, 144.1, 143.7, 141.0, 139.1, 139.1, 139.0, 135.6, 132.7, 132.1, 129.6, 125.9, 123.4, 122.0, 122.0, 119.7, 117.1, 116.6, 116.3, 115.7, 115.6, 113.4, 111.6, 107.0, 106.8, 106.6, 105.0, 84.4, 84.3, 79.7, 79.6, 79.5, 72.9, 67.1, 67.0, 45.3, 44.1, 42.4, 42.2, 31.0, 29.8, 29.7, 28.6, 28.5, 28.2, 28.1, 25.1, 25.1, 25.1, 22.7, 22.6, 21.3, 13.6, 13.6, 13.5. MS (ESI) m/z: [M + H] + calcd for [C 26 H 34 N 7 O 3 ] + , 492.3; found, 492.3; HRMS (ESI) m/z: [M + H] + calcd for [C 26 H 34 N 7 O 3 ] + , 492.2718; found, 492.2715.…”