Pyrazinamide → (2S)-N-[(1R)-1-(1,3,6,2-dioxazaborocan-2-yl)-3-methylbutyl]-3-phenyl-2-(pyrazin-2-ylformamido)propanamide

Temperature

-25.5 °C

Preparation of N-[(1S)-1[[[(1R)-1-[3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]amino]carbonyl]-2-benzyl]2-pyrazine carboxamide (i.e., (1S,2S,3R,5S)-(+)-2,3-pinanediol boronic ester of Formula IV, wherein R1 is 2-pyrazinyl and R2 is benzyl). A 500 ml three neck round bottomed flask equipped with a stir bar, addition funnel, thermocouple, nitrogen inlet/outlet and cooling bath was charged with 11 g (99.9 mmol) of (S)-3-Phenyl-2-[(pyrazine-2-carbonyl)-amino]-propionic acid, 15.5.0 g (40.6 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU), 12.2 g (40.6 mmol) of (1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylamine hydrochloride salt (87:13 mixture of isobutyl diastereomers (R:S)) and 165 mL of N,N-dimethylformamide (DMF). The pale yellow reaction solution was cooled to −35° C. where 12.6 g (17 mL, 97.3 mmol) of N,N-di-isopropyl ethyl amine was added dropwise over six minutes at −34° C. to −35° C. The resulting solution was then stirred overnight at −40 to −11° C. The reaction mixture was quenched onto 600 ml of a 1:1 cold water/ethyl acetate mixture. After transferring into a separatory funnel the layers were separated. The organic phase was then washed successively with 10% aqueous sodium hydrogen phosphate (1×200 mL), 8% aqueous sodium bicarbonate (2×200 mL) and saturated sodium chloride (1×200 mL). The product solution was dried over magnesium sulfate then filtered. The filtrate was evaporated to dryness in vacuo to give 19.57 g (37 7 mmol, 93%) of the title compound as a light brown foam with an HPLC purity of 92 A %. 1H NMR (d6-DMSO, 400 MHz) δ 9.15 (d, 1H, J=1.44 Hz), 8.87 (d, 1H, J=2.48 Hz), 8.7 (m, 3H), 7.25 (m, 4H), 7.18 (m, 1H), 4.89 (q, 1H, J=6.88, 15.4 Hz), 4.13 (dd, 1H, J=1.8, 8.56 Hz), 3.15 (d, 2H, J=6.88 Hz), 2.7 (m, b, 1H), 2.22 (m, b, 1H), 2.05 (m, b, 1H), 1.87 (t, 1H, J=5.40 Hz), 1.81 (s, b, 1H), 1.67 (d, b, 1H), 1.52 (m, b, 1H), 1.13-1.33 (m, 9H), 0.83 (dd, 6H, J=2.48, 6.56 Hz), 0.80 (s, 3H).

1. temperaturethermocouple, nitrogen inlet/outlet and cooling bath
2. additionwas added dropwise over six minutes at −34° C. to −35° C
3. customThe reaction mixture was quenched onto 600 ml of a 1:1 cold water/ethyl acetate mixture
4. customAfter transferring into a separatory funnel
5. customthe layers were separated
6. washThe organic phase was then washed successively with 10% aqueous sodium hydrogen phosphate (1×200 mL), 8% aqueous sodium bicarbonate (2×200 mL) and saturated sodium chloride (1×200 mL)
7. dry with materialThe product solution was dried over magnesium sulfate
8. filtrationthen filtered
9. customThe filtrate was evaporated to dryness in vacuo

ORD record

ord-6e315cc689e940f28657a713fc1abd7f

Source dataset

uspto-grants-2013_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08541590B2