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ethyl 5-bromo-2-methyl-pyridine-3-carboxylate[ No CAS ]
3-bromo-1,6-naphthyridin-5(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91.9%
The NAPH starting material for the synthesis of Compound A was synthesized according to Scheme 9, Route 1 by the following procedure. The jacket temperature of a 6 L jacketed reactor, Reactor 1, was set to 22 C. 2409 g (1.0 equiv) of ethyl 5-bromo-2- methylnicotinate, 824 g (1.0 equivalent) of <strong>[290-87-9]triazine</strong>, and 3.6 L dimethyl sulfoxide (DMSO) were added to the reactor. The jacket temperature was adjusted to 45 C. The reactor was agitated until a homogenous solution resulted. Once complete dissolution has occurred (visually) the jacket of Reactor 1 was cooled to 22 C.[00280] A second, 60 mL reactor, Reactor 2, was prepared. 8.0 L of water was charged to a scrubber. 4.0 L of 10 N sodium hydroxide was added to the scrubber and the scrubber was connected to Reactor 2. The cooling condenser was started. 6411.2 g of cesium carbonate and 12.0 L of DMSO were added to Reactor 2. Agitation of Reactor 2 was initiated. The batch temperature of Reactor 2 was adjusted to 80 C. The solution from Reactor 1 was added slowly over 1 h at 80 C, while monitoring the internal temperature. 1.2 L of DMSO was added to Reactor 1 as a rinse. The DMSO rinse was transferred from Reactor 1 to Reactor 2 over 6 mm. Reactor 2 was agitated for more than 1 h and the conversion to 3-bromo-1,6-naphthyridin-5(6H)- one was monitored by HPLC until there was 1.0% ethyl 5-bromo-2-methylnicotinate remaining. When the reaction was complete the batch temperature was adjusted to 60 C. 24.0(1OV) of water was added to Reactor 2 over 2 h, maintaining a reaction temperature of 60±5C, using a peristaltic pump at 192 mL/min. Reactor 2 was cooled to 22 C over 1 h 10 mm. Stuffing was continued at 22±5 C until the supernatant assays for less than 3mg/mL of 3-bromo- 1,6-naphthyridin-5(6H)-one (analyzed by HPLC). The crystallized product was filtered through an Aurora filter fitted with 25 tm polypropylene filter cloth. The reactor and filter cake were washed with a 75 wt% H20-DMSO solution (3 Vol made from 1.6 L DMSO and 5.6 L water), followed by water (7.2 L, 3 Vol), and finally toluene (7.2 L, 3 Vol). The product cake was dried on the aurora filter under vacuum with a nitrogen stream at ambient temperature. The product was determined to be dry when the KF was <2.0 wt% water. 2194 g of 3-bromo-1,6- naphthyridin-5(6H)-one was isolated as a beige solid. The chemical purity was 99.73%. The adjusted yield was 2031.6 g (9 1.9%).
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