5-Bromonicotinamide

Off-white to light pink powder

General procedure: Following the amide intermediate Preparation Example A. The reaction vessel is closed (when the amide intermediate has a boiling point at normal pressure equal to or lower than the reaction temperature TB described below) or the reaction vessel is kept open (when the amide intermediate has a boiling point higher than the normal pressure When the reaction temperature is TB), the stirring is continued (600 r/min), the reaction temperature is changed to TB, and after the reaction temperature TB is maintained for TD hours, the reaction is almost complete. Then, the reaction vessel was sealed and connected to a vacuum pump so that the degree of vacuum in the reaction vessel reached 20-50 mbar (according to the type of nitrile product) and the distillate was used as the nitrile product. The yield of the nitrile product was calculated and sampled for nuclear magnetic proteomics and elemental analysis to characterize the nitrile product obtained. Specific reaction conditions and characterization results are shown in Tables A-7, A-8, A-9, A-10 and A-11 below. These characterization results show that the nitrile product obtained has an extremely high purity (above 99percent).In these nitrile product preparation examples, 10 g of diphosphorus pentoxide was optionally added to the reaction vessel as a catalyst at the start of the reaction.EXAMPLE P; 3-Bromo-5-fluoropyridine; Step 1; 3-Amino-5-bromopyridine; To a ice-cold solution of 31.8 g (0.79 mol) of Sodium hydroxide and 40.7 g (0.255 mol) of Bromine in 340 ml of water were added 42.0 g (0.209 mol) of commercially available 5-Bromonicotinamide. The mixture was allowed to warm up to room temperature and then heated for 1 h at 70° C. The resulting brown suspension was allowed to cool to room temperature. The aqueous phase was saturated with brine and extracted three times with a 1:1 mixture of THF and t-Butyl-methyl ether. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vaccuo. Concentration in vaccuo yielded 39.1 g of a dark brown residue which was purified by flash chromatography (heptane/ethyl acetate 1:1) to yield the title compound as a brown solid (total 70.2 g, 70percent)Step 1: 3-Amino-5-bromopyridine To a ice-cold solution of 31.8 g (0.79 mol) of Sodium hydroxide and 40.7 g (0.255 mol) of Bromine in 340 ml of water were added 42.0 g (0.209 mol) of commercially available 5-Bromonicotinamide. The mixture was allowed to warm up to room temperature and then heated for 1 h at 70° C. The resulting brown suspension was allowed to cool to room temperature. The aqueous phase was saturated with brine and extracted three times with a 1:1 mixture of THF and t-Butyl-methyl ether. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vaccuo. Concentration in vaccuo yielded 39.1 g of a dark brown residue which was purified by flash chromatography (heptane/ethyl acetate 1:1) to yield the title compound as a brown solid (total 70.2 g, 70percent), MS (ISP): m/e=173.1, 175.1 (M+H+).To a solution of NaOH (22.9 g, 572 mmol) in water (245 mL) at 0-5° C. (ice salt bath) was added bromine (9.44 mL, 184 mmol) maintaining the temperature at 0-5° C., to produce a sodium hypobromite solution. To this NaOBr-sol. was added commercially available Example 23B 3-amino-5-bromopyridine A solution of 3M NaOH (250 mL) at room temperature was treated with bromine (25.9 g, 162 mmol), stirred for 15 minutes, treated with Bromine (18.76 g, 117.4 mmol) was added to a solution of sodium hydroxide (23.88 g, 597 mmol) in water (200 mL). To this solution was added In a microwave reaction vessel 3a (1.01 g, 5.00 mmol, 1.00 equiv) was mixed with styrene (651 mg, 6.25 mmol, 1.25 equiv), tris( o-tolyl)phosphine (61 mg, 0.20 mmol, 0.04 equiv), Pd2(dba)3 (92 mg, 0.10 mmol, 0.02 equiv) and NEt3 (863 MuL, 0.63 g, 6.25 mmol, 1.25 equiv) and suspended in anhydrous DMF (6 mL). The reaction was conducted at 120 °C for 40 min in a microwave reactor. After cooling to room temperature the mixture was taken up in EtOAc and filtered through a pad of Celite®. The filtrate was washed with water (3 × 30 mL) and sat. aq. NaCl solution (30 mL), dried over MgSO4 and concentrated under reduced pressure. The formed precipitate was collected by filtration and recrystallized from EtOAc. The product was obtained as colourless crystals (0.55 g, 2.45 mmol, 49percent): Rf= 0.25 (cyclohexane/THF 1:1); mp: 196.4 °C; 1H NMR (400 MHz, DMSO-d6) delta(ppm) 8.93 (d, J= 2.0 Hz, 1H), 8.90 (d, J= 2.1 Hz, 1H), 8.50 (pseudo-t, J= 2.0 Hz, 1H), 8.24 (s, br, 1H), 7.71'7.62 (m, 3H), 7.54'7.28 (m, 5H); 13C NMR, DEPT135, HSQC, HMBC (75.5 MHz, DMSO-d6) delta (ppm) 166.4, 150.4, 147.3, 136.4, 132.4, 131.4, 131.3, 129.6, 128.7, 128.2, 126.7, 124.2; IR (ATR) nu (cm'1): 3372, 3168, 1649, 1619, 1492, 1394, 961, 746, 691, 568; HRESIMS: calcd for [C14H12N2O + H]+ 224.0950, found 224.0939; comp. purity (220 nm): 100 percent; anal. calcd for C14H12N2O: N, 12.49; C, 74.98; H, 5.39; found: N, 12.38; C, 74.81; H, 5.15.Synthesis was conducted according to the procedure of 2b using 3a (603 mg, 3.00 mmol, 1.00 equiv), 1-(benzyloxy)-3-vinylbenzene (946 mg, 4.50 mmol, 1.50 equiv), tris(o-tolyl)phosphine (91 mg, 0.30 mmol, 0.10 equiv), Pd(OAc)2 (34 mg, 0.15 mmol, 0.05 equiv) and NEt3 (1.25 mL, 913 mg, 9.00 mmol, 3.00 equiv) in anhydrous DMF (4 mL). The reaction was conducted at 140 °C for 1.5 h in a microwave reactor. The raw product was recrystallized from ACN yielding a colourless solid (328 mg, 0.99 mmol, 33percent)

Molecular Weight:201.02
XLogP3:0.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:199.95853
Monoisotopic Mass:199.95853
Topological Polar Surface Area:56
Heavy Atom Count:10
Complexity:140
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes