5-Chloro-3-methylpicolinic acid

A 10 L bottle was charged with dichloropyridine, palladium acetate, dppf (1, 1'-Bis(diphenylphosphino)ferrocene), and TEA in methanol 6 L. The bottle was stirred then contents transferred to an 5 gallon stainless steel stirred reaction vessel (Kla=1.42 (at) 40percent fill and 1000 rpm) via vacuum. The bottle was rinsed with another 2 L methanol, and the rinse was added to reaction vessel by the same method. The vessel was tested for leaks using nitrogen, then purged with nitrogen three times and carbon monoxide three times with the final carbon monoxide charge to be 50 psig of Carbon monoxide. The pressurized vessel was heated to a temperature of 100° C. The agitation rate was 1000 rpm. The reaction was allowed to progress for eleven hours, then allowed to cool to room temperature and sampled. Reaction was judged to be complete when 3percent LCAP or less of starting material remained. Batch was transferred to a 50 L r.b. flask equipped with a thermocouple and stir paddle. Flask was connected to a batch concentrator and concentration begun at approximately 25-30 in Hg of applied vacuum. Intermittent heating of batch was applied to maintain temp at approximately 30-35° C. Concentration was discontinued when copious precipitate was noted. Saturated brine 20 L was added via addition funnel over one hour. Batch was aged with gentle stirring overnight. In morning, a methanol/ice bath was applied to cool batch to -5° C. for 1.5 hours. Solids were collected by filtration and rinsed with 5 L brine twice, then dried under nitrogen tent overnight to give 3.47 Kg of product intimately mixed with sodium chloride: 57 wt percent, 1.98 Kg of product in the isolated solids, 99percent yield, ML losses 0.41percent. The product can be stored at this point if desired. NMR 1H δ: 3.87 (s, 3H), 7.69 (dd, J=8.4, 2.4 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 8.54 (d, J=2.4 Hz, 1H). NMR 13C δ: 52.8, 125.8, 135.7, 136.6, 145.7, 148.6, 164.6. Solids and tetrahydrofuran were charged to a 50 L r.b. flask equipped with stir paddle. The batch was stirred for one hour, at which point the water content (Kf) of the batch was less than 1000 ug/0.5 mL. The batch was concentrated with incremental tetrahydrofuran addition to azeotropically dry to Kf of 780 ug/0.5 mL. HPLC assay was 122 mg/g of THF solution, 1.97 Kg product in 16.06 Kg of solution.To a solution of 5-chloro-3-methylpicolinonitrile (24.0 g, 157 mmol) in EtOH (100 mL) was added NaOH 5. ON (110 ml, 550 mmol). The resulting mixture was refluxed at 90 °C for 18 h. After cooling to RT, the reaction mixture was conentrated, diluted with water and the pH of the solution was adjusted to 4 by addition of 5N HC1. The solid that precipitated was filtered and set aside. The filtrate was extracted with EtOAc (2X). The aqueous layer was again acidified with 5N HC1 to pH 4 and extracted with EtOAc (2X). The EtOAc extracts were combined, dried, and concentrated. The solid obtained from all the workup steps were combined and dried in a high vac oven at 40 °C for 12 h to give the title compound 5-chloro-3-methylpicolinic acid (24.1 g, 140 mmol, 89 percent yield). LC/MS (ESf ) m/z = 172.0 (M+H)To a solution of 5-chloro-3-methylpicolinonitrile (24.0 g, 157 mmol) in EtOH (100 mL) was added NaOH (110 mL of 5 N solution, 550 mmol). The resulting mixture was refluxed at 90° C. for 18 h. After cooling to RT, the reaction mixture was concentrated. The residue was diluted with water and the pH of the solution was adjusted to 4 by addition of 5 N HCl. The solid that precipitated was filtered and set aside. The filtrate was extracted with EtOAc (2×). The aqueous layer was again acidified with 5 N HCl to pH 4 and extracted with EtOAc (2×). The EtOAc extracts were combined, dried, and concentrated. The solid obtained from all the workup steps were combined and dried in a high vac oven at 40° C. for 12 h to give 5-chloro-3-methylpicolinic acid (268) (24.1 g, 140 mmol, 89percent yield). LC/MS (ESIA mixture of 2-bromo-5-chloro-3-methylpyridine (45 g, 218 mmol), zinc cyanide (8.30 mL, 131 mmol), tris(dibenzylideneacetone) dipalladium (0) (4.99 g, 5.45 mmol), and 1 , 1’-bis(diphenylphosphino)ferrocene (6.04 g, 10.90 mmol) in dimethylacetamide (40 mL) was heated to 110 °C for 4 h. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic phase obtained was concentrated under reduced pressure and residue purified by chromatography on silica gel using ISCO eluting with 0-60percent EtOAc/hexanes to afford 5-chloro-3-methylpicolinonitrile (25.4 g, 166 mmol, 76 percent yield). LC/MS (ESI

Molecular Weight:171.58
XLogP3:1.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:171.0087061
Monoisotopic Mass:171.0087061
Topological Polar Surface Area:50.2
Heavy Atom Count:11
Complexity:163
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes