4-amino-2-chloro-5-fluoropyridine

4-Amino-2-chloro-5-fluoropyridine (12). A mixture of 2-chloro-5-fluoro-4-nitropyridine-1-oxide (11, 1.3 g, 6.8 mmol) and 1.6 g of Raney nickel in 80 mL of anhydrous ethyl alcohol was hydrogenated at 40 psi in a Parr hydrogenation apparatus for 3 h when TLC showed that the starting material had disappeared and a new spot was detected (CH2Cl2/EtOAc, 4:1, v/v, Rf 0.78 and 0.71, for the starting material and the product, respectively). The catalyst was removed by filtration and washed carefully with ethyl alcohol. The filtrate and washings were combined and evaporated in vacuo to give 0.9 g (91percent) of product as an off-white solid. A small analytical sample was purified by recrystallization from hot water to afford white crystals: mp 110-111° C.; 1H NMR (CDCl3) δ 4.50 (br s, 2H, NH2, D2O exchangeable), 7.15 (d, 1H, 3-H, J=6 Hz), 7.95 (d, 1H, 6-H, J=2 Hz). Analysis calculated for C5H4ClFN2: C, 40.97; H, 2.75; N, 19.12. Found: C, 41.18; H, 2.39; N, 18.89.A mixture of 2-chloro-5-fluoro-4-nitropyridine-l-oxide (0.75 g, 3.9 mmol) and 0.8 g of Raney nickel in 40 niL of anhydrous ethyl alcohol was hydrogenated at 40 psi in a Parr hydrogenation apparatus for 3 hrs when TLC showed that the starting material had disappeared and a new product spot was detected. The catalyst was removed by filtration and washed carefully with ethyl alcohol (2 x 20 niL). Combined filtrate was evaporated in vacuo to give the desired product 4-Amino-2-chloro-5-fluoropyridine (0.25 g, yield: 44percent). 3/4 NMR (CDC14-Amino-2-chloro-5-fluoropyridine (12). A mixture of 2-chloro-5-fluoro-4-nitropyridine-1-oxide (11, 1.3 g, 6.8 mmol) and 1.6 g of Raney nickel in 80 mL of anhydrous ethyl alcohol was hydrogenated at 40 psi in a Parr hydrogenation apparatus for 3 h when TLC showed that the starting material had disappeared and a new spot was detected (CH2Cl2/EtOAc, 4:1, v/v, Rf 0.78 and 0.71, for the starting material and the product, respectively). The catalyst was removed by filtration and washed carefully with ethyl alcohol. The filtrate and washings were combined and evaporated in vacuo to give 0.9 g (91percent) of product as an off-white solid. A small analytical sample was purified by recrystallization from hot water to afford white crystals: mp 110-111° C.; 1H NMR (CDCl3) δ 4.50 (br s, 2H, NH2, D2O exchangeable), 7.15 (d, 1H, 3-H, J=6 Hz), 7.95 (d, 1H, 6-H, J=2 Hz). Analysis calculated for C5H4ClFN2: C, 40.97; H, 2.75; N, 19.12. Found: C, 41.18; H, 2.39; N, 18.89.A mixture of 2-chloro-5-fluoro-4-nitropyridine-l-oxide (0.75 g, 3.9 mmol) and 0.8 g of Raney nickel in 40 niL of anhydrous ethyl alcohol was hydrogenated at 40 psi in a Parr hydrogenation apparatus for 3 hrs when TLC showed that the starting material had disappeared and a new product spot was detected. The catalyst was removed by filtration and washed carefully with ethyl alcohol (2 x 20 niL). Combined filtrate was evaporated in vacuo to give the desired product 4-Amino-2-chloro-5-fluoropyridine (0.25 g, yield: 44percent). 3/4 NMR (CDC14-Amino-2-chloro-5-fluoropyridine (12). A mixture of 2-chloro-5-fluoro-4-nitropyridine-1-oxide (11, 1.3 g, 6.8 mmol) and 1.6 g of Raney nickel in 80 mL of anhydrous ethyl alcohol was hydrogenated at 40 psi in a Parr hydrogenation apparatus for 3 h when TLC showed that the starting material had disappeared and a new spot was detected (CH2Cl2/EtOAc, 4:1, v/v, Rf 0.78 and 0.71, for the starting material and the product, respectively). The catalyst was removed by filtration and washed carefully with ethyl alcohol. The filtrate and washings were combined and evaporated in vacuo to give 0.9 g (91%) of product as an off-white solid. A small analytical sample was purified by recrystallization from hot water to afford white crystals: mp 110-111 C.; 1H NMR (CDCl3) delta 4.50 (br s, 2H, NH2, D2O exchangeable), 7.15 (d, 1H, 3-H, J=6 Hz), 7.95 (d, 1H, 6-H, J=2 Hz). Analysis calculated for C5H4ClFN2: C, 40.97; H, 2.75; N, 19.12. Found: C, 41.18; H, 2.39; N, 18.89.A mixture of 2-chloro-5-fluoro-4-nitropyridine-l-oxide (0.75 g, 3.9 mmol) and 0.8 g of Raney nickel in 40 niL of anhydrous ethyl alcohol was hydrogenated at 40 psi in a Parr hydrogenation apparatus for 3 hrs when TLC showed that the starting material had disappeared and a new product spot was detected. The catalyst was removed by filtration and washed carefully with ethyl alcohol (2 x 20 niL). Combined filtrate was evaporated in vacuo to give the desired product 4-Amino-2-chloro-5-fluoropyridine (0.25 g, yield: 44%). ¾ NMR (CDC13, 400 MHz) delta 7.95 (d, J = 2.0 Hz, 1H), 6.65 (d, J= 6.0 Hz, 1H), 4.52 (br s, 2H). LCMS(ESI) m/z: 1 13.4 [M+H+].A microwave vial charged with 2-Chloro-5-fluoropyridin-4-amine (500 mg, 3.41 mmol) and (S)-3-Methylmorpholine (3102 pi, 27.3 mmol) was heated in the microwave at 210 C for 52 hours. The crude product was concentrated onto celite and purified on the Biotage (reverse phase silica gel) eluting with 0-50% ACN/H2O. The desired fractions were collected, concentrated and dried under high vacuum at RT to afford (S)-5-fluoro-2-(3- methylmorpholino)pyridin-4-amine (2.94 mmol, 86 % yield) as a sticky brown solid. 1 H NMR (500MHz, DMSO-d6) d = 7.70 (d, J=3.1 Hz, 1 H), 5.96 (d, J=6.4 Hz, 1 H), 5.85 (s, 2H), 4.1 1 - 4.05 (m, 1 H), 3.87 (dd, J= 3.5, 1 1 .1 Hz, 1 H), 3.68 - 3.64 (m, 1 H), 3.61 - 3.56 (m, 1 H), 3.51 (dd, J=2.1 , 12.8 Hz, 1 H), 3.43 (dt, J=3.1 , 1 1 .6 Hz, 1 H), 2.92 (dt, J= 3.7, 12.4 Hz, 1 H), 1 .02 (d, J= 6.6 Hz, 3H); LCMS (m/z): 212.4 [M+1 ]+.2-(5-chloro-2-methoxy-phenyl)acetic acid (753 mg, 3.75 mmol) in thionyl 1 mL, 68.24 mmol) was stirred at 70 C for 1 hour. The resulting mixture was to dryness and azeotroped with toluene (2 x 10 mL). The crude residue was DMF (10 mL) and treated dropwise with a solution of 2-chloro-5-fluoro-pyridin- 0 mg, 3.41 mmol) in DMF (3 mL) followed by DIPEA (1.49 mL, 8.53 mmol). at room temperature under an inert atmosphere for 16 hours, the mixture was tOAc (100 mL) and washed with water (2 x 50 mL) and brine (2 x50 mL). The on was dried over Na2SO4 and concentrated in vacuo. The crude material was 18 reverse phase chromatography eluting with 0-100% MeCN in water with acid modifier to afford the titled compound as a light yellow solid. 0 MHz, DMSO-d6) delta 10.58 (s, 1H), 8.41 (d, J = 2.7 Hz, 1H), 8.24 (d, J = 5.6 3-7.28 (m, 2H), 7.01 (d, J = 9.5 Hz, 1H), 3.83 (s, 2H), 3.75 (s, 3H). hod E): Rt 1.25 mins; MS m/z 328.9, 330.9= [M+H]+The residue obtained in the 1st step and a sodium methoxide solution (5M methanol solution) (5 ml) were added to a tube and the tube was sealed, followed by stirring at 170C for 3 hours. The reaction solution was adjusted to room temperature. Sodium hydroxide (49 mg) was added, followed by stirring at 170C for 1 hour. The reaction solution was adjusted to room temperature, the solvent was distilled away under reduced pressure, and a saturated aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate. Subsequently, the resultant was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane : ethyl acetate = 4:1 to 1:1), and yellow oily matter of 3-fluoro-2-methoxypyridin-4-amine (27 mg) was thus obtained. MS (ESI m/z): 143 (M+H) RT (min): 0.41

Molecular Weight:146.55
XLogP3:1.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:146.0047040
Monoisotopic Mass:146.0047040
Topological Polar Surface Area:38.9
Heavy Atom Count:9
Complexity:101
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes