2-Amino-N-(5-chloro-2-pyridinyl)-5-methoxybenzamide

Compound A (30 g, 1.0 eq) was suspended in methanol (300 ml, 10 vol), ferric chloride (1.58 g, 0.1 eq) was added, heated to reflux, and hydrazine hydrate (80percent, 24.4 g, 4.0 eq) was slowly added dropwise under reflux, and keep warm for 6 h. The reaction was monitored by HPLC to a raw material peak area <0.3 percent. After the reaction is completed, most of the solvent is concentrated under reduced pressure and lowered to room temperature. Add ethyl acetate and stir for 1 h. Washed with water, separated, washed with saturated brine and dried over anhydrous sodium sulfate. Concentrate to dryness under reduced pressure to give a pale yellow solid. Purity > 98percent, yield 93percent.To a 780 L Hastelloy reactor, compound C (33 Kg, 1.0 eq), 5percent platinum carbon (sulfided, 0.33 Kg, 0.010 parts) and dichloromethane (578 Kg, 17.5 parts) were charged. Agitation was started and reactor contents were adjusted to 22° C. (19 to 25° C.). The reactor was pressurized with ca. 30 psi hydrogen and the reaction mixture gently heated to 28° C. (25-31° C.). Hydrogenation of the reactor contents was performed under ca. 30 psi at 28° C. (25 to 31° C.; maximum 31° C.) until the reaction was complete by HPLC. After 16.5 hrs, the reaction was deemed complete after confirming the disappearance of starting material (0.472 A percent). The contents of the reactor were circulated through a conditioned celite pad (0.2-0.5 Kg celite conditioned with 20-55 Kg dichloromethane) prepared in a 8 sparkler filter to remove the platinum catalyst. The reactor and celite bed were rinsed forward with two portions of dichloromethane (83 Kg, 2.5 parts each). The filtrate was transferred to and concentrated in a 570 L GLMS reactor under a atmospheric pressure to ca. 132 L (4 parts volume). Ethanol (69 Kg, 2.1 parts) was charged and concentration continued under atmospheric pressure to ca. 99 L (3 parts volume). In-process NMR indicated that the dichloromethane content was 39percent. Ethanol (69 Kg, 2.1 parts) was charged again and concentration continued again to ca. 99 L (3 parts volume). In-process NMR indicated that the dichloromethane content was 5percent. The reaction mixture was then adjusted to 3° C. (0 to 6° C.), agitated for ca. 1 hr, and the resulting slurry filtered onto a jacketed pressure nutsche fitted with F-19 filter cloth. The reactor, pump, and lines were rinsed forward with cold [3° C. (0-6° C.)] ethanol (26 Kg, 0.8 parts). The wet filter cake (36.6 Kg) was dried under vacuum at 40-50° C. with a maximum temperature of water bath (to heat reactor jacket) of 50° C. LOD analysis after 12.5 hrs indicated solvent content was at 0.1percent. The dry product (D) was discharged (26.4 Kg) in 89.5percent yield. HPLC showed 98.4 A percent purity, with dechlorinated impurity at 0.083percent.Step 2. Synthesis of 2-amino-N-(5-chloro-pyridin-2-yl)-5-methoxy-benzamide (D)To a 780 L Hastelloy reactor, compound C (33 kg, 1.0 eq.), 5percent platinum carbon(sulfided, 0.33 kg, 0.010 parts) and dichloromethane (578 kg, 17.5 parts) were charged. Agitation was started and reactor contents were adjusted to 22 To a 780 L Hastelloy reactor, compound C (33 kg, 1.0 eq.), 5percent platinum carbon (sulfided, 0.33 kg, 0.010 parts) and dichloromethane (578 kg, 17.5 parts) were charged. Agitation was started and reactor contents were adjusted to 22° C. (19-25° C.). The reactor was pressurized with ca. 30 psi hydrogen and the reaction mixture gently heated to 28° C. (25-31° C.). Hydrogenation of the reactor contents was performed under ca. 30 psi at 28° C. (25 to 31° C.; maximum 31° C.) until the reaction was complete by HPLC. After 16.5 hrs, the reaction was deemed complete after confirming the disappearance of starting material (0.472 A percent). The contents of the reactor were circulated through a conditioned celite pad (0.2-0.5 kg celite conditioned with 20-55 kg dichloromethane) prepared in a 8 sparkler filter to remove the platinum catalyst. The reactor and celite bed were rinsed forward with two portions of dichloromethane (83 kg, 2.5 parts each). The filtrate was transferred to and concentrated in a 570 L GLMS reactor under a atmospheric pressure to ca. 132 L (4 parts volume). Ethanol (69 kg, 2.1 parts) was charged and concentration continued under atmospheric pressure to ca. 99 L (3 parts volume). In-process NMR indicated that the dichloromethane content was 39percent. Ethanol (69 kg, 2.1 parts) was charged again and concentration continued again to ca. 99 L (3 parts volume). In-process NMR indicated that the dichloromethane content was 5percent. The reaction mixture was then adjusted to 3° C. (0 to 6° C.), agitated for ca. 1 hr, and the resulting slurry filtered onto a jacketed pressure nutsche fitted with a filter cloth. The reactor, pump, and lines were rinsed forward with cold [3° C. (0-6° C.)]ethanol (26 kg, 0.8 parts). The wet filter cake (36.6 kg) was dried under vacuum at 40-50° C. with a maximum temperature of water bath (to heat dryer jacket) of 50° C. LOD analysis after 12.5 hrs indicated solvent content was at 0.1percent. The dry product (D) was discharged (26.4 kg) in 89.5percent yield. HPLC showed 98.4 A percent purity, with dechlorinated impurity at 0.083percent.Exam le 4. Synthesis of 2-amino-N-(5-chloro-pyridin-2-yl)-5-methoxy-benzamideProcess A[0116] To a 780 L Hastelloy reactor, Compound C (33 kg, 1.0 eq.), 5percent> platinum carbon (sulfided, 0.33 kg) and dichloromethane (578 kg) were charged. Agitation was started and reactor contents were adjusted to 22 °C (19-25 °C). The reactor was pressurized with ca. 30 psi hydrogen and the reaction mixture gently heated to 28 °C (25-31 °C). Hydrogenation of the reactor contents was performed under ca. 30 psi at 28 °C (25 to 31 °C; maximum 31 °C) until the reaction was complete by HPLC. After 16.5 hrs, the reaction was deemed complete after confirming the disappearance of starting material (0.472 Apercent). The contents of the reactor were circulated through a conditioned Celite.(TM). (diatomaceous earth; Celite Co., Santa Barbara, Ca.) pad (0.2-0.5 kg Celite.(TM). conditioned with 20-55 kg dichloromethane) prepared in a 8' sparkler filter to remove the platinum catalyst. The reactor and Celite.(TM). bed were rinsed forward with two portions of dichloromethane (83 kg). The filtrate was transferred to and concentrated in a 570 L glass-lined reactor under an atmospheric pressure to ca. 132 L. Ethanol (69 kg) was charged and concentration continued under atmospheric pressure to ca. 99 L. In-process NMR indicated that the dichloromethane content was 39percent. Ethanol (69 kg) was charged again and concentration continued again to ca. 99 L. In-process NMR indicated that the dichloromethane content was 5percent. The reaction mixture was then adjusted to 3 °C (0 to 6 °C), agitated for ca. 1 hr, and the resulting slurry filtered onto a jacketed pressure nutsche fitted with a filter cloth. The reactor, pump, and lines were rinsed forward with cold [3 °C (0-6 °C)] ethanol (26 kg. The wet filter cake (36.6 kg) was dried under vacuum at 40-50 °C with a maximum temperature of water bath (to heat dryer jacket) of 50 °C. LOD analysis after 12.5 hrs indicated solvent content was at 0.1percent. The dry product (B) was discharged (26.4 kg) in 89.5percent yield. HPLC showed 98.4 Apercent purity, with dechlorinated impurity at 0.083 percent.General procedure: To a stirring solution of 13a (5 g, 0.016 mol) in 50 mL ethyl acetate at 25-30 °C was added stannous chloride dihydrate (18 g, 0.08 mol). After stirring at same temperature for 2 h, reaction mixture was diluted with ethyl acetate (10 v/w) and made alkaline with aqueous ammonia solution. Reaction mixture was then filtered through hyflow bed and organic layer was dried over sodium sulfate. Evaporation of solvent afforded 14a (3.2 g, 71percent) as pale yellow solidGeneral procedure: A mixture of compound 2a (1.0g, 3.3mmol) and 81 Pd/C (10percent, 0.1g) in 82 ethanol (15mL) was stirred under 1atm of 83 HStir at room temperature, N-(5-chloro-pyridin-2-yl)-5-methoxy-2-nitro-benzamide 45.6g(Compound C, 0.15 mol, 1.0 eq) was dissolved in 450 ml of acetic acid.83.7 g (1.5 mol, 10 eq) of iron powder was added in portions; after the iron powder was added, the reaction was stirred for 3 hours.Then add 1000 ml of ethyl acetate and 500 ml of water.Separation; the separated aqueous phase was treated with ethyl acetate 500 ml × 2)Extract twice; combine the organic phases, followed by water, Saturated aqueous solution of sodium bicarbonate, Wash with saturated aqueous sodium chloride solution, Dry over anhydrous sodium sulfate, Concentration under reduced pressure gave Compound D (37.5 g).General procedure: Under nitrogen in 500mL dry two-necked flask was added 2-amino-5-chloropyridine (11.98g, 93.19mmol), potassium tert-butoxide (20.91g, 186.38mmol), anhydrous tetrahydrofuran (300mL) at 23 after stirring at 27 ~ clear solution, three times added 5-methoxy-isatoic anhydride (18.00g, 93.19mmol), after the addition was completed, at 23 ~ 27 reaction was stirred 1.0 ~ 1.5h, TLC (V petroleum ether: V ethyl acetate = 2: 1) after completion of the reaction is monitored; was added purified water (50mL) was stirred for 0.5 ~ 1.0h, the reaction solvent was distilled off under reduced pressure, evaporated after completion, ethyl acetate (400mL), saturated sodium carbonate solution ( 400mL), stirred for 10 ~ 15min, phases were separated, the aqueous phase was extracted with ethyl acetate (300mL × 2), the organic phase was collected, dried over anhydrous sodium sulfate was added (100g), dried 2h. By filtration, the filtrate was collected, the solvent evaporated under reduced pressure to give a pale yellow solid (22.05g, 85.20percent).

Molecular Weight:277.70
XLogP3:2.5
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:277.0618043
Monoisotopic Mass:277.0618043
Topological Polar Surface Area:77.2
Heavy Atom Count:19
Complexity:316
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes