Pyridine → N-(5-Chloropyridin-2-yl)-5-methoxy-2-nitrobenzamide
Reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8]([OH:10])=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>O.C(#N)C>[N+:12]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:7]=1[C:8]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1)=[O:10])([O-:14])=[O:13]Participants
Conditions
- Temperature
- 25 °C
Procedure
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.
Workup
- customwas adjusted to 22° C.
- additionwas added
- washThe pump and lines were rinsed forward with acetonitrile (22.5 Kg, 0.9 parts)
- customwere adjusted to a temperature of 19-22° C
- washThe metering pump and lines were rinsed forward with acetonitrile (12.5 Kg, 0.5 parts)
- customat 25° C.
- custom(22-28° C.)
- additionafter the addition of about ⅓ of the POCl3
- additionAt the end of the addition, it
- additionAfter complete addition
- customreaction completion
- temperatureThe solution was cooled to 15° C. (12-18° C.)
- additionwas charged slowly
- customreaction temperature between 12 and 30° C
- customwas then adjusted to 22° C.
- custom(19 to 25° C.)
- stirringagitated for ca. 5 hrs
- filtrationthe contents of the reactor were filtered onto a pressure nutsche
- customfitted with F-19 filter cloth
- washThe reactor, pump, and lines were washed forward onto the pressure nutsche with two portions of drinking water (62.5 Kg, 2.5 parts each)
- dry with materialThe product (41.8 Kg) was dried under vacuum with a maximum temperature of water bath
- temperature(to heat reactor jacket) of 50° C
- waitAfter ca. 12 hrs
Sources & evidence
- ORD record
- ord-b46d269ae1d64d78b3c79ef6f0bb2a1f
- Source dataset
- uspto-grants-2013_10
- Patent number
- US08557852B2
Reaction notes
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