4-AMINO-2-FLUORO-N-METHYLBENZAMIDE

Methyl 4-amino-2-fluoro-benzylamide A solution of 2, 4-difluoro-benzoylchloride D in a solution of methylamine and tetrahydrofuran (THF) is allowed to react to produce 2, 4-difluoro-N-methylbenzamide M (quantitative yield). The 2, 4-difluoro-N-methylbenzamide M is mixed with in a solution of acetonitrile and 4-methoxy-benzenemethanamine and heated in a microwave for 20 minutes at 190° C. to produce 2-fluoro-4-(4-methoxybenzylamino)-N-methylbenzamide S (yield of 40percent). The 2-fluoro-4-(4-methoxybenzylamino)-N-methylbenzamide S is reacted in a solution of dichloromethane and trifluoroacetic acid to produce 2-fluoro-4-amino-N-methylbenzamide T (yield greater than 95percent). The 2-fluoro-4-amino-N-methylbenzamide T is reacted with a solution of sodium cyanide and cyclobutanone to produce 4-(1-cyanocyclobutylamino)-2-fluoro-N-methylbenzamide B.Synthesis of 4-Amino-2-fluoro-N-methyl-benzamide 4a. [00194] To a solution of 2-fluoro-N-methyl-4-nitro-benzamide 21 (3g, 15.1mmol) in co-solvent of ethyl acetate and acetic acid (12mL+12mL) was added iron dust (8g, 143.mmol). The suspension was heated at reflux until the starting material disappeared in LCMS. Cooled down to 25°C. The solid was filtered off and the filtrate was diluted with ethyl acetate (50mL). The organic phase was washed with brine (3x30mL), dried (MgS0A mixture of N-methyl-2-fluoro-4-nitrobenzamide (52a) (2.89 g, 14.6 mmol) and iron(5.04 g, 90 mmol) in ethyl acetate (40 ml) and acetic acid (40 ml) was refluxed for 1 hour. The solid particles were filtered off. The filtrate was washed with water and extracted with ethyl acetate. The organic layer was dried over MgSOA mixture of N-Methyl-2-fluoro-4-nitrobenzamide (Formula 38) (0.18 g, 0.91 mmol) and iron (0.31 g, 5.60 mmol) in ethyl acetate (5 mL) and acetic acid (5 mL) was refluxed for 1 h. Charge 100g of 2-Fluoro-N-methyl-4-nitrobenzamide and 500ml of methanol into the 1L autoclave at ambient temperature. To this add, 35 ml of Encapsulated Raney Ni (previously washed with water) and 3g of acetic acid. Close the autoclave and flush with nitrogen for 2 times and then pressurized with hydrogen to 5.0 Kg and maintain until completion of the reaction. After completion of the reaction filter the catalyst and wash with 50 ml of methanol. Concentrate the filtrate to remove the methanol under vacuum at 45-50°C to a thick residue and add 300 ml of water, stir slurry for lh and filter, wash with 50 ml of water. Dry the product and dry wt is 70g (83.3percent).To a solution of compound 7 (14.6g, 73.7mmol) in EA (100ml) and AcOH (9.2ml, 0.50mol) was added Fe (39g) portion-wise under NSynthesis of 2-fluoro-N-methyl-4-amino-benzamide (Compound 5) Compound 7 (14.6 g, 73.7 mmol) was dissolved in a solution of ethyl acetate and acetic acid (50 ml: 50 ml). Iron powder (39 g) was added. The resulting mixture was refluxed overnight for 16 h, and then cooled to room temperature. The solid was filtered and washed three times with ethyl acetate (3x50 ml). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated the residue was purified by column chromatography (DCM:MeOH=50:1)to give a pale yellow solid of compound 8 (7.62 g, 61.5percent yield). ‘H NMR (CDC13, 400 MHz): ö 7.92 (1H, m), 6.60 (1H, s), 6.49 (1H, d, J=8.4 Hz), 6.32 (1H, d, J=14 Hz), 4.10 (2H, s), 2.99 (3H, s) ppm.N-Methyl 2-flouro-4-nitro benzamide (Formula VI; 13 g) was added to methanol(260 mL) followed by the addition of 10percent (w/w) palladium/carbon (1.3 g) at 27°C andhydrogen gas at 2 Kg/cm2 to 2.5 Kg/cm2 pressure for 2 hours to 4 hours. The reaction mixture was filtered through celite and washed with methanol (40 mL). The solution obtained was concentrated under reduced pressure at 30°C to 35°C for 1 hour to 2 hours to obtain the title compound.Yield: 10.5 g.In a 500 mL four necked round bottomed flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, (20 g) In a 500 mL four necked round bottomed flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, (20 g) General procedure: To a stirred solution of various substituted amines 2 (10 mmol) and NaHCO3 (3.10 g, 37 mmol) in the mixed solution of ethyl acetate/water=1/1 (20 mL), bromoacetyl bromide (3.84 g, 23 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and the solvent was evaporated in vacuo to give 3a-3j.Compound I (100 g, 0.594 mol) is suspended in 300 mL of dioxane. TEA (250 mL, 3.59 mol) is added by pouring in a thin stream. The system is placed under nitrogen, and heated to 60C. A solution of intermediate II (160 g, 0.90 mol) in 150 mL of dioxane is prepared separately. The solution of compound II is added to the suspension in the reactor and left to react for about 20 hours. The mixture is cooled to l5C and filtered through a Biichner funnel, washing the cake twice with 100 mL of dioxane each time. The resulting product is suspended in 1200 mL of water, 1M HC1 is added until a pH < 3 is reached, and the resulting suspension is then filtered through a Buchner funnel, washing the cake twice with 200 mL of water each time. The crystal thus isolated is dried under vacuum at the temperature of 60C, providing intermediate III in a 76% yield (120 g, 45.1 mmol) and 99.6% HPLC purity. NMR (300MHz, CDCh) d 15.3 (m, 4H), 2.58 (t, br, 2H), 2.73 (s, 3H), 6.00 (m, 1 H), 6.22 (s, 1 H), 7.17 (s, 1H), 7.46 (s, 1H), 7.65 (d, 1H), 12.63 (m, 1H).To a slurry of the compound of Formula (4) (5.03 g, 29.91 mmol) and the compound of Formula (3) (8.59 g, 47.99 mmol) in methylene chloride (50 mL) was added triethylamine (9.60 g, 94.87 mmol) dropwise at room temperature. The resulting mixture was allowed to stir at room temperature for 20 hours to afford a slurry. Diisopropylethylamine (7.90 g, 61.13 mmol) was then added and the mixture was heated to reflux, affording a clear solution. The reaction mixture was maintained at reflux for 4 days. Methylene chloride was removed in vacuo, and water (50 mL) was added to the residue, followed by concentrated hydrochloric acid (37 wt %; 3.8 mL). The resulting sludge-like material was stirred for 16 hours at room temperature, cooled to 2-5 C. for 4 hours, filtered and was washed with water (2×20 mL). The filter cake was dried in vacuo at room temperature for 16 hours to afford the compound of Formula (2-A) (7.3 g, 92% yield) as a beige solid.A sample (2.3 g) of this material was subjected to further purification by treatment with saturated sodium bicarbonate solution (200 mL) and methylene chloride (200 mL). The resulting biphasic system was stirred at ambient temperature for 2 hours. Prior to separation of the layers, small amounts of insoluble solids were filtered and removed. The aqueous layer was acidified to a pH of less than 3 with concentrated hydrochloric acid (37 wt %), and the resulting slurry was stirred at ambient temperature for 2 hours, filtered and was washed with water (20 mL). The filter cake was dried in vacuo at room temperature for 15 hours, and then for 24 hours at 40 C., to afford the compound of Formula (2-A) (1.3 g, 58% yield from the 2.3 g crude sample) as a yellow solid. Chromatographic purity of the purified sample (HPLC, area %): 100.0%.

Molecular Weight:168.17
XLogP3:0.6
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:168.06989108
Monoisotopic Mass:168.06989108
Topological Polar Surface Area:55.1
Heavy Atom Count:12
Complexity:174
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes