Baricitinib

The oral, targeted synthetic DMARD (tsDMARD), JAK1 and JAK2 inhibitor baricitinib (Olumiant) is a novel small molecule[1] that is approved in the EU and Japan for the treatment of adults with rheumatoid arthritis RA (moderate or severe active), who responded inadequately to (other treatments) or who were intolerant of C1 DMARD. JAK is a tyrosine kinase that plays crucial roles in cytokine receptor binding.

4-Chloro-7H-pyrrolo[2, 3-d]pyrimidine (0.8 g; Formula IX) was added into a reaction vessel containing a solution of potassium carbonate (2.1 g) in water (30 mL) at about 20°C to about 25°C. A solution of { l-(ethylsulfonyl)-3-[4-(4, 4, 5, 5-tetramethyl- l, 3, 2-dioxaborolan-2-yl)-lH-pyrazol-l-yl]azetidin-3-yl}acetonitrile (2.0 g; Formula V) in 1, 4-dioxane (30 mL) was added into the reaction mixture at about 20°C to about 25 °C, followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.1 g). The reaction mixture was stirred at about 80°C to about 85°C for about 5 hours. On completion of the reaction, 1, 4-dioxane was recovered from the reaction mixture under reduced pressure at about 45°C to obtain a residue. Ethyl acetate (50 mL) was added into the residue, and then the contents were stirred for about 5 minutes. The organic and aqueous layers were separated. The organic layer was concentrated under reduced pressure at about 45°C to obtain baricitinib. Yield: 99.0percentCompound 5 (0.092g, 0 . 24mmol), compound 11 (0.037g, 0 . 24mmol), cesium fluoride (0.129g) and Pd (PPh 2~yl)-lH-pyrazol-l-yl]azetidm-3-yl}acetonitrile (5.00 g, 13.15 mmol), potassium phosphate tribasic (2.80 g, 13.19 mmol) and a mixture of dichloro[l, - bis(dicyclohexylphosphino)ferrocene] palladium(ll) with potassium phosphate tribasic (2.84 g of the mixture containing 50 mg total with 0.07 mmol palladium catalyst). THF (21 mL) is added to the autoclave followed by water (5.3 mL). The autoclave is sealed and the contents are heated to 90 °C for 19 hours. The reaction mixture is cooled and the resulting suspension is diluted with THF (40 mL) and water (10 mL). The solution is filtered through a mixture of diatomaceous earth (0.4 g) and carbon (0.2 g). The filtrate is concentrated under vacuum to remove THF. An aqueous buffer solution (pH = 7, 30 mL) is added followed by l-butanol (30 mL). The mixture is heated to 85 °C with stirring to dissolve residual solids. Stirring is stopped and the lower aqueous layer is removed. Water (10 mL) is added to the stirred l-butanol layer. Stirring is discontinued and the lower aqueous layer is removed. The l-butanol layer is cooled to 75 °C and stirred for 30 minutes. The solution is further cooled to 20 °C over 6 hours and the resulting slurry is held at that temperature overnight. The solids are collected by filtration, washed with 9: 1 v/v 1 -butane i/water (10 mL) and dried at 40 °C to give the title compound (3.45 g, 70.6percent). The title compound (2.5 g, 6.73 mmol) is combined with l-butanol (12.6 mL) and water (3.8 mL). The mixture is heated to 85 °C and stirred for 30 minutes. The solution is cooled to 20 °C over 7 hours to provide a slurry. The solids are collected by filtration then washed with 1-butanol followed by water. The solids are dried to give the title compound (2.25 g, 90percent after recrystallization of 2.5 g).To a flask were added 2-{1-(ethylsulfonyl)-3-[4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (12) (870 mg, 2.3 mmol, 1.1 equiv.), 4-chloro-7-H-pyrrolo[2, 3-d]pyrimidine (5) (290 mg, 0.19 mmol), caesium fluoride (1120 mg), tetrakis(triphenylphosphine)palladium (240 mg, 0.1 equiv.), tertbutanol (10 mL), water (10 mL) and toluene (10 mL) at ambient temperature. The resulting reaction mixture was heated to reflux under nitrogen for 48 h. Then the reaction mixture was cooled to room temperature and filtered through a Celite bed. The Celite bed was washed with ethyl acetate and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure to remove solvents and the crude product was purified by flash chromatography on a silica gel column eluting with methanol in dichloromethane (0–60percent) to afford baricitinib: Yield 560mg (84percent); m.p. 193–195 °C; IR: 3203, 3113, 2998, 2847, 2363, 1584, 1328, 1137 cm–1. Anal. calcd for C16H17N7O2S: C, 51.74; H, 4.61; N, 26.40; found: C, 51.91; H, 4.49; N, 26.57percent. MS (m/z): 372 [M + H]+;1H NMR (300 MHz, DMSO-d6): δ 1.25 (t, J = 7.3 Hz, 3H), 3.23 (m, J= 7.3 Hz, 2H), 3.69 (s, 2H), 4.24 (d, J = 9.0 Hz, 2H), 4.61 (d, J = 9.0 Hz, 2H), 7.08 (s, 1H), 7.62 (s, 1H), 8.47 (s, 1H), 8.71 (s, 1H), 8.92 (s, 1H), 12.12 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 7.4, 24.9, 39.3, 43.4, 58.5, 99.9, 113.0, 116.6, 126.9, 129.5, 139.9, 149.3, 150.9, 152.2.200 g of acetonitrile and 20.4 g (0.05 mol) of compound 4 were added to a 1 L reaction flask. 6.9 g (0.05 mol) was added with stirring. Potassium carbonate was stirred at room temperature for 30 min, then 9.3 g (0.05 mol) of compound 7 and 8 g (0.05 mol) of DBU were added. The temperature of the system is raised to 40 ° C After the reaction for 8 hours, the reaction was completed, and the reaction of the starting materials was completed, and the reaction was stopped. Evaporate the solvent under reduced pressure and add to the system. After quenching the reaction with 100 g of water, 200 g of ethyl acetate was added. Stir for 30 min, filter, and rinse the cake with 100 g of fresh ethyl acetate. The filter cake was dried to give a white solid of 17.0 g, HPLC ≥ 99.0percent, yield: 91.2percent.A solution of 2-(3-(4-(5, 5-dimethyl-1, 3, 2-dioxaborate-2-yl)-1H-pyrazol-1-yl)-1(ethylsulfonyl)azetidin-3-yl)acetonitrile (36.62 g, 1OO mmol)4-chloro-7H-pyrrolo[2, 3-d]pyrimidine (16.12 g, 105 mmol)Cesium carbonate (52.92 g, 150 mmol), N, N-dimethylacetamide (180 mL) and water (36 mL)Stirring dissolved after vacuum switch nitrogen 3 times, Palladium acetate (113 g, 0.5 mmol) was added under nitrogen atmosphere, Ligand XtanPhos(289 mg, 0.5 mmol), And then vacuum switch nitrogen 3 times, Then heated to 95 ~ 100 ° C for 5-6 hours, The reaction was quenched by adding water (180 mL) and the mixture was extracted twice with ethyl acetate (180 mL). The combined organic phase was washed twice with water (180 mL), filtered through celite and concentrated to recrystallize with isopropanol and water Biti products (27. llg, 73percent).A suspension of (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)methyl pivalate (20, 1.0 g, 2.06 mmol) in methanol (MeOH, 5 mL) and tetrahydrofuran (THF, 20 mL) was treated with a 1 M aqueous sodium hydroxide solution (NaOH, 2.3 mL, 2.3 mmol, 1. 12 equiv) at room temperature, and the resulting reaction mixture was stirred at room temperature for 2-3 h. When HPLC showed that the reaction was deemed complete, the reaction mixture was quenched with water (10 mL) and a 1 N aqueous HCl solution (0.2 mL) to adjust pH to 7-7.5 at room temperature. The resulting mixture was stirred at room temperature for 30 min before the solids were collected by filtration. The solids were washed with a mixture of acetonitrile and water (2/3 by volume, 2.x.4 mL) and dried in vacuum at 40-45° for 24 h to afford crude 2-(3-(4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (14, 658 mg, 765 mg theoretical, 86percent yield) as off-white solids, which was found to be identical to the material prepared by Method A. For crude 14: 4-(1-(3-(Cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-lH-pyrazol-4-yl)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)methyl pivalate (1 g), methanol (5 mL), tetrahydrofuran (20 mL), and 1M sodium hydroxide (2.3 mL) were added into a reaction vessel at 20°C to 25 °C. The reaction mixture was stirred for 3 hours. Progress of the reaction was monitored by thin layer chromatography. On completion, the reaction mixture was quenched by adding water (20 mL). The pH was adjusted to 7.0 to 7.5 by adding IN hydrochloric acid, followed by completely recovering the solvent under reduced pressure at 40°C to 50°C. A sticky material was obtained. Water (10 mL) was added to the sticky material at 20°C to 25°C. The contents were stirred for 10 minutes. A solid material was precipitated out. The solid material was filtered, washed with water (20 mL), and then dried under reduced pressure at 40°C to 45°C for 24 hours to obtain the amorphous form of baricitinib. Yield: 81percent.To a solution of 2-(1-(ethylsulfonyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (6, 327 g, 655 mmol) in acetonitrile (3 L) and water (300 mL) was added LiBFA solution of equimolar amounts of baricitinib (40 mg) and A-lactic acid (9.7 mg) in 10 mL methylethylketone (MEK) was prepared. Then the solvent was slowly evaporated in a crystallization dish ( h=30mm d= 50mm) at ambient conditions (T=20C, p= l0l3mbar rH= 30%). After three days, clear colorless needle-shaped crystals grew in the solution. The crystals were separated and dried on filter paper at 40C.

Baricitinib is a JAK1 and JAK2 inhibitor and have been used as a promising treatment for rheumatoid arthritis.