Pyridine → N-(5-Chloropyridin-2-yl)-5-methoxy-2-nitrobenzamide

Participants

Reaction Conditions

Reaction Steps

5-Methoxy-2-nitrobenzoic acid (A) (25.0 Kg, 1.0 eq), 2-amino-5-chloropyridine (B) (16.3 Kg, 1.0 eq), and acetonitrile (87.5 Kg, 3.5 parts) were charged to a 380 L GLMS reactor. The reaction mixture was adjusted to 22° C. (19 to 25° C.) and anhydrous pyridine (30.0 Kg, 3.0 eq) was added. The pump and lines were rinsed forward with acetonitrile (22.5 Kg, 0.9 parts), and the reactor contents were adjusted to a temperature of 19-22° C. Phosphorous oxychloride (23.3 Kg, 1.20 eq) was charged to the contents of the reactor via a metering pump, while maintaining a temperature of 25° C. (22-28° C.). The metering pump and lines were rinsed forward with acetonitrile (12.5 Kg, 0.5 parts), while keeping the temperature at 25° C. (22-28° C.). The reaction mixture normally turned from a slurry to a clear solution after the addition of about ⅓ of the POCl3. At the end of the addition, it became turbid. After complete addition, the reaction mixture was agitated at 25° C. (22-28° C.) for ca. 1 hr, at which time HPLC analysis confirmed reaction completion. The solution was cooled to 15° C. (12-18° C.) and drinking water (156.3 Kg, 6.25 parts) was charged slowly while keeping reaction temperature between 12 and 30° C. The reaction mixture was then adjusted to 22° C. (19 to 25° C.) and agitated for ca. 5 hrs until exotherm ceased. Formation of a slurry was visually confirmed and the contents of the reactor were filtered onto a pressure nutsche fitted with F-19 filter cloth. The reactor, pump, and lines were washed forward onto the pressure nutsche with two portions of drinking water (62.5 Kg, 2.5 parts each). The filtrate had a pH value of 7. The product (41.8 Kg) was dried under vacuum with a maximum temperature of water bath (to heat reactor jacket) of 50° C. After ca. 12 hrs, in-process LOD analysis indicated a solvent content of 0.72%. The dry product (C) was discharged (34.4 Kg) with 88.2% yield and 99.1% purity by HPLC.

Provenance & Evidence