Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 1187594-09-7 | MDL No. : | MFCD27920779 |
Formula : | C16H17N7O2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XUZMWHLSFXCVMG-UHFFFAOYSA-N |
M.W : | 371.42 | Pubchem ID : | 44205240 |
Synonyms : |
LY3009104;INCB028050
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 80 - 85℃; for 5 h; | 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: 99.0percent |
90% | With tetrakis(triphenylphosphine) palladium(0); cesium fluoride In water; toluene; <i>tert</i>-butyl alcohol at 100℃; for 48 h; Inert atmosphere | Compound 5 (0.092g, 0 . 24mmol), compound 11 (0.037g, 0 . 24mmol), cesium fluoride (0.129g) and Pd (PPh 3) 4 (0.028g) adding toluene, tertiary butyl alcohol and water (1:1:1) in the mixed solvent, nitrogen protection, 100 °C reflux reaction 48 hours, cooling to room temperature, a diatomite filter. Ethyl acetate for flushing diatomite, collect filtrate, separating organic layer, the aqueous layer extracted with ethyl acetate, the organic layer concentrated, drying, column chromatography purification to obtain white solid 0.060g, yield 90percent. |
90% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In tetrahydrofuran; water at 90℃; for 19 h; Autoclave; Inert atmosphere | 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). |
84% | With tetrakis(triphenylphosphine) palladium(0); cesium fluoride In water; toluene; <i>tert</i>-butyl alcohol for 48 h; Reflux; Inert atmosphere | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.2% | Stage #1: With potassium carbonate In acetonitrile at 20℃; for 0.5 h; Stage #2: With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 40℃; for 8 h; |
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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With palladium diacetate; caesium carbonate; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane In N,N-dimethyl acetamide; water at 95 - 100℃; Inert atmosphere | 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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: With water; sodium hydroxide In tetrahydrofuran; methanol at 20℃; for 2 - 3 h; Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water at 20℃; for 0.5 h; |
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: 1H NMR (DMSO-d6, 300 MHz) δ 12.15 (s, 1H), 8.94 (s, 1H), 8.72 (s, 1H), 8.49 (s, 1H), 7.63 (d, 1H), 7.09 (d, 1H), 4.62 (d, 2H), 4.25 (d, 2H), 3.71 (s, 2H), 3.24 (q, 2H), 1.26 (t, 3H) ppm; C16H17N7O2S (MW, 371.42), LCMS (EI) m/e 372 (M++H). |
81% | With sodium hydroxide In tetrahydrofuran; methanol at 20 - 25℃; for 3 h; | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.8% | Stage #1: With lithium tetrafluoroborate; water In acetonitrile at 75℃; Stage #2: With ammonium hydroxide; water In acetonitrile at 0 - 10℃; |
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 LiBF4 (614 g, 6.55 mol, 10.0 equiv). The resulting reaction mixture was stirred at 75° C. for overnight. The reaction mixture was cooled to 0° C. before a solution of ammonium hydroxide (NH4OH, 570 mL) in water (2.2 L) was added slowly to keep the temperature below 10° C. (pH 9-10). The mixture was stirred at room temperature for overnight. When the reaction was deemed complete, water (10 L) was added and the resulting mixture was vigorously stirred for 3 h at room temperature. The solids were collected by filtration, washed with water (6.7 L) and heptane (6.7 L), and dried in vacuum oven at 45° C. over the weekend. The dried solid was then dissolved in 20percent MeOH in dichloromethane (12 L), and was purified by column chromatography on 1.3 Kg of silica gel eluting with a 20percent MeOH in dichloromethane solution (18L) to afford 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (7, 204 g, 243.3 g theoretical, 83.8percent yield) as an off-white solid. For 7: 1H NMR (300 MHz, d6-DMSO) δ 1.25 (t, 3H), 3.25 (q, 2H), 3.75 (s, 2H), 4.25 (d, 2H), 4.65 (d, 2H), 7.10 (d, 1H), 7.65 (dd, 1H), 8.50 (s, 1H), 8.70 (s, 1H), 8.95 (s, 1H), 12.2 (bs, 1H); MS: m/z calcd. 372.12; found: 372.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.2% | With phosphoric acid In methanol; water; acetonitrile at 68℃; for 1 h; | Baricitinib (0.30 g; 0.8 nimol) was dissolved in acetonitrile (7 ml) under boiling and during30 minutes, a solution of phosphoric acid (0.20 g; 2.1 equivalents; 85percent cone. in water) inmethanol (1.2 ml) was added by dripping. The obtained suspension was stirred for 1 hour at the temperature of 68°C, then it was slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off and dried at 35°C and 200 mbar for 18h. Baricitinib phosphate of form C was obtained as white powder (376 mg; 99.2percent). Stoichiometry 1:1.14. |
93% | With phosphoric acid In ethanol; acetonitrile at 70℃; for 2 h; | To a solution of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (7, 204 g, 550 mmol) in acetonitrile (5.1 L) and ethanol (1.6 L) was added a solution of phosphoric acid (67.4 g, 688 mmol, 1.25 equiv) in ethanol (800 mL) slowly over 30 min at 70° C. The resulting reaction mixture was stirred at 70° C. for 2 h before being gradually cooled to room temperature with stirring for overnight. The solids were collected by filtration, washed with acetonitrile (160 mL) and dried in vacuum oven at 45° C. for 6 h to afford 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile phosphoric acid salt (240 g, 258.2 g theoretical, 93percent yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.8% | 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 LiBF4 (614 g, 6.55 mol, 10.0 equiv). The resulting reaction mixture was stirred at 75 C. for overnight. The reaction mixture was cooled to 0 C. before a solution of ammonium hydroxide (NH4OH, 570 mL) in water (2.2 L) was added slowly to keep the temperature below 10 C. (pH 9-10). The mixture was stirred at room temperature for overnight. When the reaction was deemed complete, water (10 L) was added and the resulting mixture was vigorously stirred for 3 h at room temperature. The solids were collected by filtration, washed with water (6.7 L) and heptane (6.7 L), and dried in vacuum oven at 45 C. over the weekend. The dried solid was then dissolved in 20% MeOH in dichloromethane (12 L), and was purified by column chromatography on 1.3 Kg of silica gel eluting with a 20% MeOH in dichloromethane solution (18L) to afford 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (7, 204 g, 243.3 g theoretical, 83.8% yield) as an off-white solid. For 7: 1H NMR (300 MHz, d6-DMSO) delta 1.25 (t, 3H), 3.25 (q, 2H), 3.75 (s, 2H), 4.25 (d, 2H), 4.65 (d, 2H), 7.10 (d, 1H), 7.65 (dd, 1H), 8.50 (s, 1H), 8.70 (s, 1H), 8.95 (s, 1H), 12.2 (bs, 1H); MS: m/z calcd. 372.12; found: 372.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | 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, 2×4 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, 86% yield) as off-white solids, which was found to be identical to the material prepared by Method A. For crude 14: 1H NMR (DMSO-d6, 300 MHz) delta 12.15 (s, 1H), 8.94 (s, 1H), 8.72 (s, 1H), 8.49 (s, 1H), 7.63 (d, 1H), 7.09 (d, 1H), 4.62 (d, 2H), 4.25 (d, 2H), 3.71 (s, 2H), 3.24 (q, 2H), 1.26 (t, 3H) ppm; C16H17N7O2S (MW, 371.42), LCMS (EI) m/e 372 (M++H). | |
81% | With sodium hydroxide; In tetrahydrofuran; methanol; at 20 - 25℃; for 3h; | 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 20C 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 40C to 50C. A sticky material was obtained. Water (10 mL) was added to the sticky material at 20C to 25C. 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 40C to 45C for 24 hours to obtain the amorphous form of baricitinib. Yield: 81%. |
With sodium hydroxide; In tetrahydrofuran; methanol; water; at 20 - 30℃; | Add in 250mL round bottom reaction bottles(4-(1-(3-(Cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[ 2,3,d]pyrimidin-7-yl)methyl pivalate(4.00g),THF (80 mL),Methanol (20mL),9.2 mL of a 1 M aqueous sodium hydroxide solution was added dropwise with stirring.After the drop,Stir at 20 to 30 C until TLC detects the disappearance of the raw materials.Add 60mL of water,1M hydrochloric acid solution conditions pH to 7 ~ 8. 45 C under reduced pressure to remove most of the organic solvent,Stir at 20 to 30 C overnight.Filter, drain,Vacuum drying at 45 C to obtain 2.79 g of crude barrickinib.The yield was 91%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.2% | With phosphoric acid; In methanol; water; acetonitrile; at 68℃; for 1h; | Baricitinib (0.30 g; 0.8 nimol) was dissolved in acetonitrile (7 ml) under boiling and during30 minutes, a solution of phosphoric acid (0.20 g; 2.1 equivalents; 85% cone. in water) inmethanol (1.2 ml) was added by dripping. The obtained suspension was stirred for 1 hour at the temperature of 68C, then it was slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off and dried at 35C and 200 mbar for 18h. Baricitinib phosphate of form C was obtained as white powder (376 mg; 99.2%). Stoichiometry 1:1.14. |
93% | With phosphoric acid; In ethanol; acetonitrile; at 70℃; for 2h;Product distribution / selectivity; | To a solution of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (7, 204 g, 550 mmol) in acetonitrile (5.1 L) and ethanol (1.6 L) was added a solution of phosphoric acid (67.4 g, 688 mmol, 1.25 equiv) in ethanol (800 mL) slowly over 30 min at 70 C. The resulting reaction mixture was stirred at 70 C. for 2 h before being gradually cooled to room temperature with stirring for overnight. The solids were collected by filtration, washed with acetonitrile (160 mL) and dried in vacuum oven at 45 C. for 6 h to afford 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile phosphoric acid salt (240 g, 258.2 g theoretical, 93% yield) as a white solid. |
With phosphoric acid; In ethanol; acetonitrile; at 70℃; for 2h; | 2.2 g of Barrickinib was suspended in a mixed solvent of 54 ml of acetonitrile and 20 ml of ethanol (technical grade), and the suspension was heated to 70 C, and the suspension was completely dissolved, and 0.9 g of phosphoric acid (85%, 1.3 eq) was dissolved. After 7 ml of ethanol, the solution was slowly added dropwise, stirred at 70 C for 2 hours, slowly lowered to room temperature (over 150 minutes), and stirred at room temperature until every other day, filtered, and washed with 10 ml of acetonitrile, 30 Drying under vacuum at C for 5 days gave a white solid which, after detection, was the crystalline form D of Barrickinib and its melting point was 180.1 to 181.5 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80 - 85℃; for 5h; | 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 20C to about 25C. 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 20C to about 25 C, followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.1 g). The reaction mixture was stirred at about 80C to about 85C for about 5 hours. On completion of the reaction, 1,4-dioxane was recovered from the reaction mixture under reduced pressure at about 45C 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 45C to obtain baricitinib. Yield: 99.0% |
90% | With tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In water; toluene; tert-butyl alcohol; at 100℃; for 48h;Inert atmosphere; | Compound 5 (0.092g, 0 . 24mmol), compound 11 (0.037g, 0 . 24mmol), cesium fluoride (0.129g) and Pd (PPh 3) 4 (0.028g) adding toluene, tertiary butyl alcohol and water (1:1:1) in the mixed solvent, nitrogen protection, 100 C reflux reaction 48 hours, cooling to room temperature, a diatomite filter. Ethyl acetate for flushing diatomite, collect filtrate, separating organic layer, the aqueous layer extracted with ethyl acetate, the organic layer concentrated, drying, column chromatography purification to obtain white solid 0.060g, yield 90%. |
90% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 90℃; for 19h;Autoclave; Inert atmosphere; | 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, 70.6%). 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, 90% after recrystallization of 2.5 g). |
84% | With tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In water; toluene; tert-butyl alcohol; for 48h;Reflux; Inert atmosphere; | 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 (0-60%) to afford baricitinib: Yield 560mg (84%); 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, 26.57%. MS (m/z): 372 [M + H]+;1H NMR (300 MHz, DMSO-d6): delta 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): delta 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With hydrogenchloride; In ethanol; at 40 - 45℃; | Three-necked flaskCompound 8 (47.15 g, 100 mmol),Anhydrous ethanol (236 mL) was added,After stirring, 2 mol / L hydrochloric acid in ethanol (50 mL, 100 mmol) was added,Plus heating after heating to 40 ~ 45 C reaction 2 ~ 3 hours.After the reaction, a small amount of product seed crystals were added and slowly cooled to room temperature, filtered, ethanol (47 mL), the filter cake was transferred to another flask, dichloromethane (236 mL) was added, 5% sodium carbonate solution (236 mL) The aqueous phase was extracted twice with methylene chloride (118 mL). The organic phases were combined with saturated brine (118 mL). Twice, dried over sodium sulfate, filtered and concentrated. The solvent was dried in vacuo to give an off-white solid. 10 (34.54 g, 93%). |
93% | With hydrogenchloride; In ethanol; at 40 - 45℃; | A solution of 4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (47.15 g, 1OO mmol) was added anhydrous ethanol (236 mL). After stirring, 2 mol / L hydrochloric acid ethanol solution (50 mL, lOO mmol) was added and heated To 40 ~ 45 C reaction 2 ~ 3 hours. After the reaction, a small amount of product seed crystals were added and slowly cooled to room temperature, filtered, ethanol (47 mL), the filter cake was transferred to another flask, dichloromethane (236 mL) was added, 5% sodium carbonate solution (236 mL) The aqueous phase was extracted twice with dichloromethane (118 mL), washed twice with organic phase, saturated brine (118 mL), concentrated by filtration,Recrystallization from a mixed solvent of ethanol and water gave a white solid valitidine (34.54 g, 93%). |
92.7% | In water; butan-1-ol; at 90℃; | tert-Butyl 4- (1 -[3-(cyanornethyl)- I -(ethylsuifonyl)azetidin-3-yf-1 H-pyrazoi-4- yl}-7H-pyrroio[2,3-d]pvrimidine-7-carboxylate (2.0 g. 4,2 mmol) is suspended in a mixture of I -butanol (13.0 mL) and water (4.0 ml), and heated to 90 C with stirring, The resulting light yellow solution is stirred at 9() C until less than 1% starting material remains by FIPLC analysis (typically about 4 hours), The solution is allowed to slowlycool to 20-25 C over several hours, After two more hours at room temperature, the solid is collected by vacuum filtration, washed with I -butanol (5 ml), and dried in vacuo at 40C overnight to provide the title compound as a white solid (1,46 g. 92.7%), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In water; N,N-dimethyl-formamide; at 85 - 90℃;Inert atmosphere; | The compound 5b (33.32 g, 100 mmol) was added to the three-necked flask,Compound 8b (25.73 g, 105 mmol),Potassium phosphate(42.45 g, 200 mmol),N, N-dimethylformamide (167 mL) and water (33 mL)After stirring, the nitrogen was removed three times under vacuum, and Pd (dppf) cl2 (1.46 g, 2 mmol) was added under nitrogen.And then vacuum to switch nitrogen 3 times, and then heated to 85 ~ 90 C reaction 5-6 hours, the end of the reaction by adding water (167mL), the mixture by adding ethyl acetate (167mL) extraction 2 times, combined organic phase washed 2 times 167 mL), dried over sodium sulfate, and the product was separated by column chromatography with validine 10 (28.23 g, 76%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 50 - 55℃; | A solution of 2-(1-(ethylsulfonyl)-3-(4-(7-p-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyridine-yl)-3-azetidin-3-yl)acetonitrile (52.56 g, 1OO mmol) A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 mil / L, 200 mL) was added,Plus after heating to 50 ~ 55 C reaction 3 ~ 4 hours.After completion of the reaction, the water quenching reaction was added,And then decompression to spin most of the solvent,Adding dichloromethane to 260mL,The aqueous phase was extracted again with dichloromethane (130 mL)The combined organic phases were washed twice with saturated brine (130 mL)Filtration and concentration, adding isopropyl alcohol and water beating, and drying by filtration to give valerinib (30.83 g, 83%) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl acetamide; water; at 95 - 100℃;Inert atmosphere; | 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, 73%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.36% | In acetonitrile; at 20 - 22℃; for 2h; | 1.00 g (2.69 mmol) of { 1-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3-djpirimidin-4-yl)-1H- pyrazol-1-yljazetidin-3-yl}acetonitrile (baricitinib) is measured into 40 ml of acetonitrile at 20-22 C, then while stirring a solution of 0.27 g (2.96 mmol; 1.1 equiv.) of oxalic acid made with 10 ml of acetonitrile is added to it drop by drop. The reaction mixture is stirred for 2 hours at 20-22 C. The precipitated solid material is filtered, washed on the filter withacetonitrile, then dried in the air at atmospheric pressure until constant weight is achieved. In this way 0.70 g (56.36%) of a white coloured solid product is obtained.Mp.: 184.1 C (peak maximum).JR (KBr): 3113, 2656, 2259, 1625, 1583, 1345, 1142.1H-NMR (DMSO-d6, 400 MHz): 12.20 (bs, 1H), 8.95 (s, 1H), 8.74 (s, 1H), 8.50 (s, 1H), 7.65 (dd, 11=2.4 Hz, 12=3.5 Hz, 1H), 7.11 (dd, 11=1.5 Hz, 12=3.5 Hz, 1H), 4.62 (d, 1=9.2 Hz, 2H), 4.27 (d, 1=9.3 Hz, 2H), 3.71 (s, 2H), 3.25 (q, 1=7.4 Hz, 2H), 1.26 (t, 1=7.3 Hz, 3H).13C-NMR (DMSO-d6, 100 MHz): 161.27, 152.39, 150.95, 149.41, 140.13, 129.88, 127.26,122.23, 116.86, 113.25, 100.23, 58.75, 56.30, 43.56, 27.04, 7.64.Element analysis calculated for the formula C18H19N7O6S (M 461.45):C 46.85%; H 4.15%; N 21.25%; S 6.95%Measured: C 46.72%; H 4.17%; N 21.16%; S 6.97%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.7% | In acetonitrile; at 20 - 22℃; for 3h; | 5.85 g (15.57 mmol) of { 1 -(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3-djpirimidin-4-yl)- 1H- pyrazol-1-yljazetidin-3-yl}acetonitrile (baricitinib) is measured into 150 ml of acetonitrile at20-22 C, then while stirring a mixture of 1.98 g (17.33 mmol; 1.1 equiv.) of ptoluenesulfonic acid made with 20 ml of acetonitrile is added to it drop by drop. The reaction mixture is stirred for 3 hours at 20-22 C. The precipitated solid material is filtered, washed on the filter with acetonitrile, then dried in a drying cabinet at 24 C and at a pressure of 150- 200 mbar for 24 hours. In this way 8.28 g (96.7%) of a white coloured solid product isobtained.Mp.: 22 1,2 C (peak maximum).JR (KBr): 3062, 2250, 2811, 1595, 1317, 1149.?H-NMR (DMSO-d6, 400 MHz): 13.24 (b, 1H), 9.22 (s, 1H), 9.04 (s, 1H), 8.69 (s, 1H), 8.01 (m, 1H), 7.49 (d, 1=8.0 Hz, 2H), 7.45 (m, 1H), 7.12 (-d, 1=7.9 Hz, 2H), 4.60 (d,1=9.2 Hz, 2H), 4.30 (d, 1=9.2 Hz, 2H), 3.25 (q. 1=7.3 Hz, 2H), 2.29 (s, 3H), 1.25 (t,1=7.3 Hz, 3H).?3C-NMR (DMSO-d6, 100 MHz): 152.09, 146.03, 140.55, 131.96, 130.89, 116.66, 112.68, 102.80, 58.59, 56.82, 43.69, 26.98, 7.62.Element analysis calculated for the formula C23H25N70552 (M 543.62):C 50.82%; H 4.64%; N 18.04%; 5 11.80%Measured: C 50.83%; H 4.59%; N 17.96%; 5 11.83%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.8% | In acetonitrile; at 20 - 22℃; for 4h; | 1.00 g (2, .69 mmol) { 1 -(ethylsulphonyl)-3 - [4-(7H-pyrrolo [2,3 -djpirimidin-4-yl)- 1H-pyrazol-1-yljazetidin-3-yl}acetonitrile (baricitinib) is suspended in 30 ml of acetonitrile at 20-22 C, then while stirring a solution of 0.47 g (2.97 mmol; 1.1 mol equiv.) of 2-hydroxy- ethanesulfonic acid made with 5 ml of acetonitrile is added to it drop by drop. The reaction mixture is stirred for 4 hours at 20-22 C. The precipitated solid material is filtered, washed on the filter with acetonitrile, then dried in the air at atmospheric pressure until constantweight is achieved. In this way 1.18 g (90.8%) of a white coloured solid product is obtained.Mp.: 142,9 C (onset).JR (KBr): 3455, 3111, 2671, 2249, 1628, 1595, 1158, 1029, 1322..?H-NMR (DMSO-d6, 400 MHz): 13.31 (b, 1H), 9.25 (s, 1H), 9.06 (s, 1H), 8.72 (s, 1H), 8.04 (m, 1H), 7.47 (m, 1H), 4.60 (d, 1=9.2 Hz, 2H), 4.32 (d, 1=9.2 Hz, 2H), 3.74 (s, 2H),3.66 (t, 1=6.8 Hz, 2H), 3.26 (q, 1=7.3 Hz, 2H), 2.69 (t, 1=6.8 Hz, 2H), 1.26 (t, 1=7.3 Hz, 3H).?3C-NMR (DMSO-d6, 100 MHz): 152.05, 145.31, 144.03, 140.62, 132.28, 131.42, 116.64, 115.13, 112.60, 103.18, 58.59, 57.88, 56.91, 53.87, 43.73, 26.98, 7.63Element analysis calculated for the formula C18H23N706S2 (M 497.55):C 43.45%; H 4.66%; N 19.71%; S 12.89%Measured: C 43.36%; H 4.63%; N 19.48%; S 12.99%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.7% | In acetonitrile; for 0.5h;Reflux; | 3.00 g (8.08 mmol) { 1 -(ethylsulphonyl)-3 - [4-(7H-pyrrolo [2,3 -djpirimidin-4-yl)- 1H-pyrazol-1-yljazetidin-3-yl}acetonitrile (baricitinib) is dissolved in 130 ml of acetonitrile at boiling point, then while stirring 1.03 g (8.89 mmol; 1.1 equiv.) of fumaric acid is added to it. Thereaction mixture is stirred at this temperature for 30 minutes, then left to cool to room temperature, and stirred for a further 1 hour. The precipitated solid material is filtered, washed on the filter with acetonitrile, then dried in the air at atmospheric pressure until constant weight is achieved. In this way 3.81 g (96.7%) of a white coloured solid product is obtained.Mp.: 206,5 C (peak maximum).IR (KBr): 3120, 2536, 1703, 1584, 1275, 1141.?H-NMR (DMSO-d6, 400 MHz): 13.16 (b, 2H), 12.16 (bs, 1H), 8.94 (s, 1H), 8.72 (s, 1H), 8.48 (s, 1H), 7.63 (dd, 11=2.5 Hz, 12=3.4 Hz, 1H), 7.09 (dd, 11=1.6 Hz, 12=3.5 Hz,1H), 6.64 (s, 2H), 4.61 (d, 1=9.2 Hz, 2H), 4.24 (d, 1=9.2 Hz, 2H), 3.70 (s, 2H), 3.23(q, 1=7.4 Hz, 2H), 1.25 (t, 1=7.3 Hz, 3H).?3C-NMR (DMSO-d6, 100 MHz): 166.16, 152.39, 151.09, 149.55, 140.09, 134.17, 129.78, 127.12, 122.41, 116.83, 113.25, 100.12, 58.73, 56.25, 43.55, 27.07, 7.62.Element analysis calculated for the formula C20H21N706S (M 487.49):C 49.28%; H 4.34%; N 20.11%; S 6.58%Measured: C 49.52%; H 4.32%; N 20.41%; S 6.61%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41.8% | In acetone; for 0.5h;Reflux; | 0.50 g (1.35 mmol) of { 1-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3-djpirimidin-4-yl)-1H- pyrazol-1-yljazetidin-3-yl}acetonitrile (baricitinib) is dissolved in 20 ml of acetonitrile at boiling point, then while stirring 0.27 g (1.48 mmol; 1.1 equiv.) of cyclamic acid is added to it. The reaction mixture is stirred at this temperature for 30 minutes, then left to cool to room temperature, and stirred for a further 2 hours. The precipitated solid material is filtered, then20 ml of acetonitrile and 5 ml of methanol is added to it and heated to boiling point. The mixture is left to cool to room temperature and the precipitated solid material is filtered. The product is washed on the filter with acetonitrile, then dried in the air at atmospheric pressure until constant weight is achieved. Jn this way 0.23 g (41.8%) of a white coloured solid product is obtained.Mp.: 2 17,5 C (peak maximum).JR (KBr): 3422, 1628, 1599, 1329, 1137, 1063, 617.?H-NMR (DMSO-d6, 400 MHz): 12.20 (bs, 1H), 8.95 (s, 1H), 8.72 (s, 1H), 8.49 (s, 1H), 7.69 (b), 7.64 (m, 1H), 7.10 (m, 1H), 4.60 (d, 1=9.3 Hz, 2H), 4.25 (d, 1=9.4 Hz, 2H), 3.70 (s, 2H), 3.26 (q, J=7.4 Hz, 2H), 2.95 (m, 2xlH), 1.87 (m, 2x2H), 1.62 (m,2x2H), 1.59 (m, 2xlH), 1.23 (m, 3H +2x4H), 1.10 (2xlH).?3C-NMR (DMSO-d6, 100 MHz): 152.37, 151.02, 149.48, 140.08, 129.82, 127.18, 122.33, 116.84, 113.23, 100.16, 58.72, 56.25, 49.51, 43.48, 30.52, 27.01, 24.72, 23.91,7.62.Element analysis calculated for the formula C28H43N90853 (M 729.89):C 46.08%; H 5.94%; N 17.27%.Measured: C 44.29%; H 6.44%; N 15.88%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In methanol; at 20 - 22℃; for 2h; | 1.00 g (2.69 mmol) of { 1 -(ethylsulphonyl)-3 - [4-(7H-pyrrolo [2,3 -djpirimidin-4-yl)- 1H- pyrazol-1-yljazetidin-3-yl}acetonitrile of formula (I) (baricitinib) is measured into 15 ml ofmethanol at 20-22 C, then while stirring 2.86 ml (1.1 equiv.) of a 1 M methanolic HC1 solution is added to it drop by drop. The reaction mixture is stirred for 2 hours at 20-22 C. The precipitated solid material is filtered, then dried in the air at atmospheric pressure until constant weight is achieved. In this way 1.00 g (91.1%) of a white coloured solid product is obtained. Element analysis calculated for the formula C16H18C1N7O2S (M 407.88):C 47.12%; H 4.45%; N 24.04%; S 7.86%; Cl 8.69%.Measured: C 47.03%; H 4.44%; N 23.22%; S 7.84%; Cl 8.43%.Following this 0.80 g of raw product is dissolved in 15 ml of acetonitrile at boiling point, then7 ml of methanol is added to it drop by drop at this temperature. Following this the solution is left to cool to room temperature, and stirred for two hours. The precipitated solid material is filtered, then dried in the air at atmospheric pressure until constant weight is achieved. In this way 0.32 g (40.6%) of white coloured solid product is obtained.Mp.: 240.8 C (peak maximum)JR (KBr): 2393, 1612, 1592, 1346, 1143.?H-NMR (DMSO-d6, 400 MHz): 13.42 (b, 1H), 9.47 (s, 1H), 8.98 (s, 1H), 8.94 (s, 1H), 8.03 (m, 1H), 7.51 (m, 1H), 4.60 (d,J=9.3 Hz, 2H), 4.33 (d, 1=9.3 Hz, 2H), 3.77 (s, 2H), 3.28 (q, 1=7.3 Hz, 2H), 1.26 (t, 1=7.3 Hz, 3H).?3C-NMR (DMSO-d6, 100 MHz): 152.03, 145.02, 143.80, 141.04, 132.60, 131.35, 116.63,115.09, 112.41, 103.22, 58.60, 56.88, 43.66, 26.97, 7.62.Element analysis calculated for the formula C16H18C1N7O2S (M 407.88):C 47.12%; H 4.45%; N 24.04%; 5 7.86%; Cl 8.69%.Measured: C 47.25%; H 4.36%; N 23.68%; 5 7.85%; Cl 8.37%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33.3% | In water; acetonitrile; at 20 - 22℃; for 2h; | 0.5 g (1.35 mmol) { 1 -(ethylsulphonyl)-3 - [4-(7H-pyrrolo [2,3 -djpirimidin-4-yl)- 1H-pyrazol- 1- yljazetidin-3-yl}acetonitrile (baricitinib) is suspended in 22 ml of acetonitrile at 20-22 C,then while stirring a solution of 0.22 g (1.48 mmol; 1.1 mol equiv.) of D,L-tartaric acid made with 3 ml of water is added to it drop by drop. The reaction mixture is stirred for 2 hours at 20-22 C, then evaporated until dry. 25 ml of acetonitrile is added to the residue, and then stirred for 1 hour at 20-22 C. The precipitated solid material is filtered, washed on the filter with acetonitrile, then dried in the air at atmospheric pressure until constant weight isachieved. In this way 0.1 mg (33.3%) of a white coloured solid product is obtained. JR (KBr): 3142, 2258, 1694, 1631, 1599, 1350, 1328, 1137.?H-NMR (DMSO-d6, 400 MHz): 12.57 (b, 1H), 12.15 (bs, 1H), 8.93 (s, 1H), 8.71 (s, 1H), 8.48 (s, 1H), 7.63 (dd, 11=2.4 Hz, 12=3.5 Hz, 1H), 7.09 (dd, 11=1.6 Hz, 12=3.5 Hz,1H), 4.61 (d, 1=9.2 Hz, 2H), 4.31 (s, 2H), 4.24 (d, 1=9.2 Hz, 2H), 3.70 (s, 2H), 3.24(q, 1=7.4 Hz, 2H), 1.25 (t, 1=7.3 Hz, 3H).?3C-NMR (DMSO-d6, 100 MHz): 173.32, 152.38, 151.09, 149.55, 140.09, 129.80, 127.14, 122.41, 116.85, 113.24, 100.13, 72.33, 58.73, 56.25, 43.49, 27.02,7.62.Element analysis calculated for the formula C20H23N708S (M 521.51):C 46.06%; H 4.45%; N 18.80%; S 6.15%Measured: C 44.41%; H 4.56%; N 17.96%; S 6.21%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In ethyl acetate; at 20 - 22℃; for 2h; | 1.00 g (2.69 mmol) of { 1 -(ethylsulphonyl)-3 - [4-(7H-pyrrolo [2,3 -djpirimidin-4-yl)- 1H-pyrazol-1-yljazetidin-3-yl}acetonitrile (baricitinib) is suspended in 15 ml of ethyl acetate at20-22 C, then while stirring a solution of 470 mg (2.96 mmol; 1.1 equiv.) ofbenzenesulfonic acid made with 5 ml of ethyl acetate is added to it drop by drop. The reactionmixture is stirred for 2 hours at 20-22 C, then the precipitated solid material is filtered,washed on the filter with ethyl acetate, then dried in the air at atmospheric pressure until constant weight is achieved. Jn this way 1.43 g (100%) of a white coloured solid product is obtained.The sample is spectroscopically and morphologically identical to the substance produced withmethod ?A?. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.8% | In ethyl acetate; at 20 - 22℃; for 2h; | 1.00 g (2.69 mmol) of { 1 -(ethylsulphonyl)-3 - [4-(7H-pyrrolo [2,3 -djpirimidin-4-yl)- 1H-pyrazol-1-yljazetidin-3-yl}acetonitrile (baricitinib) is suspended in 15 ml of ethyl acetate at20-22 C, then while stirring a solution of 326.2 mg (2.96 mmol; 1.1 equiv.) ofethanesulfonic acid made with 5 ml of ethyl acetate is added to it drop by drop. The reaction mixture is stirred for 2 hours at 20-22 C, then the precipitated solid material is filtered, washed on the filter with ethyl acetate, then dried in the air at atmospheric pressure until constant weight is achieved. In this way 1.28 g (98.8%) of a white coloured solid product is obtained.The sample is spectroscopically and morphologically identical to the substance produced withmethod ?A?. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.8% | In isopropyl alcohol; at 20 - 22℃; for 2h; | 1.00 g (2.69 mmol) of { 1 -(ethylsulphonyl)-3 - [4-(7H-pyrrolo [2,3 -djpirimidin-4-yl)- 1H- pyrazol-1-yljazetidin-3-yl}acetonitrile (baricitinib) is suspended in 15 ml of 2-propanol at 20- 22 C, then while stirring 191 t1 (2.96 mmol; 1.1 equiv.) of methanesulfonic acid is added to it drop by drop. The reaction mixture is stirred for 2 hours at 20-22 C, then the precipitated solid material is filtered, washed with 2-propanol on the filter, then dried in the air atatmospheric pressure until constant weight is achieved. In this way 1.23 g (97.8%) of a white coloured solid product is obtained.The sample is spectroscopically and morphologically identical to the substance produced with method ?A?. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.2% | With tetrabutyl ammonium fluoride; In 2-methyltetrahydrofuran;Reflux; | To a solution of 2- (1- (ethylsulfonyl) -3- (4- (7-benzenesulfonyl-7H- pyrrolo [2,3- d] pyrimidin-4- yl) ) Azetidin-3-yl) acetonitrile (IX, 9.23 g, 0.018 mol) in 2-methyltetrahydrofuran (100 mL)Tetramethylammonium fluoride trihydrate (7.95 g, 0.054 mol) was added,Stir the reflux overnight.The reaction mixture was concentrated to dryness under reduced pressure,With 40mL 90% ethanol beating in crude,The crude product is recrystallized from anhydrous ethanol,filter,Anhydrous ethanol,Get it after drying(Ethylsulfonyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1 H-pyrazol- 1 -yl] -3-azetidineacetonitrile(5.43 g, 81.2% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Compound 1 (150 mg, 0.40 mmol, 1 equiv) was dissolved in a mixed solvent of dichloromethane and acetonitrile, and then triethylamine (140 mL, 2.5 equiv). The reaction was allowed to react for 15 minutes in an ice-water bath. NaH (0.1 equiv) was added slowly and the mixture stirred at low temperature for half an hour. Chloromethyl butyrate (0.077 mL, 0.60 mmol, 1.5 equiv) slowly warmed to room temperature and stirred overnight. The filtrate was concentrated, mixed with silica gel and subjected to direct column chromatography (methylene chloride: methanol = 50: 1) to give Compound C-1 (129 mg) in a yield of 68%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Compound 1 (150 mg, 0.40 mmol, 1 equiv) was dissolved in a mixed solvent of dichloromethane and acetonitrile, and then triethylamine (140 mL, 2.5 equiv). The reaction was allowed to react for 15 minutes in an ice-water bath. NaH (0.1 equiv) was added slowly and the mixture stirred at low temperature for half an hour. Dimethylchlorophosphate (0.057 mL, 0.60 mmol, 1.5 equiv) was added, slowly warmed to room temperature and stirred overnight. The filtrate was concentrated, mixed with silica gel and subjected to direct column chromatography (methylene chloride: methanol = 50: 1) to give Compound E-1 (132 mg) in a yield of 68%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With Sodium trimetaphosphate; sodium carbonate; In water; at 45℃; | Compound 1 (150 mg, 0.40 mmol, 1 equiv), sodium trimetaphosphate (62 mg, 0.20 mmol, 0.5 equiv) and sodium carbonate (150 mg, 1.42 mmol, 3.5 equiv) were dissolved in water and reacted overnight at 45 C. The reaction was complete and unreacted starting material was removed by addition of sodium hydroxide (16 mg, 0.40 mmol, 1 equiv). Calcium hydroxide (30 mg, 0.40 mmol, 1 equiv) was added and the mixture was stirred at 40 C overnight. The precipitate was removed by centrifugation and the filtrate was concentrated. Compound E-2 (101 mg) was obtained by recrystallization from a 0.2 mol / L sodium hydroxide aqueous solution and ethanol (1: 2 by volume) in a yield of 51%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Compound 1 (150 mg, 0.40 mmol, 1 equiv) was dissolved in a mixed solvent of methylene chloride and acetonitrile, followed by addition of triethylamine (140 mL, 2.5 equiv). The reaction was allowed to react for 15 minutes in an ice-water bath. Acetyl chloride (0.044 mL, 0.60 mmol, 1.5 equiv) was added slowly and slowly warmed to room temperature and stirred overnight. The filtrate was concentrated, mixed with silica gel and directly purified by column chromatography (methylene chloride: methanol = 50: 1) to give Compound A-1 (106 mg) in a yield of 64%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Compound 1 (150 mg, 0.40 mmol, 1 equiv) was dissolved in a mixed solvent of dichloromethane and acetonitrile, triethylamine (140 mL, 2.5 equiv) was added and the reaction was allowed to react in an ice-water bath for 15 minutes. Isobutyryl chloride (0.084 mL, 0.60 mmol, 1.5 equiv) slowly warmed to room temperature and stirred overnight. The filtrate was concentrated, mixed with silica gel and directly purified by column chromatography (methylene chloride: methanol = 50: 1) to give Compound A-2 (128 mg) in 72% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphoric acid; In ethanol; acetonitrile; at 25℃; for 12h; | 10.2mg of phosphate crystalline Form B of compound of Formula (I) was added into a mixed solvent of 0.97 mL of acetonitrile and 0.03 mL of water to obtain a suspension, then it was stirred at 25 C. for 12 hours, centriffiged to obtain a lower layer of solid, placed the solid at a constant temperature of 25 C. for drying overnight, the obtained solid was detected as phosphate crystalline Form C. The XRPD datas of the solid prepared in this example are listed in Table 12. The XRPD pattern is displayed in FIG. 20. The DSC thermogram is displayed in FIG. 21, the TGA thermogram is displayed in FIG. 22. | |
With phosphoric acid; In water; acetonitrile; at 80℃; for 1h; | The crude barrickinib 1.0g and acetonitrile 33mL,Mixed, 0.36 g of phosphoric acid.Stir and heat to dissolve in a water bath at 80 C.Keep warm for 1 hour.Slowly cool down to 5 ~ 10 C,Stirring,Filter, drain,Drying at 50 C to obtain a crude product of barretinib phosphate 0.79 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.2% | 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 ? 99.0%, yield: 91.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.9% | With phosphoric acid; In propan-1-ol; ethanol; at 68℃; for 1.5h; | <strong>[1187594-09-7]Baricitinib</strong> (0.30 g; 0.8 rnniol) was dissolved in n-propauol (18 ml) under boiling and during30 minutes, a solution of phosphoric acid (0.22 g; 2,4 equivalents; 85% conc.) in ethanol(1,2 ml) was added by dripping. The obtained suspension was stirred for 1.5 hours at the temperature of 68C, then it was slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off and dried at 35C and 200 mbar for 1 8h. <strong>[1187594-09-7]Baricitinib</strong> hemiphosphate of form II was obtained as white powder (371 mg; 97.9%). Stoichiometry 1:0.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | In acetonitrile; at 20℃; for 18h; | <strong>[1187594-09-7]Baricitinib</strong> free base (401 mg, 1.1 mmol, e.g. prepared according to the teaching of WO2009/1 14512 Al, Examples 70 or 78) and citric acid (229 mg, 1.2 mmol) were suspended inacetonitrile (5 mL) and slurried at room temperature for 18 hours. The solid was collected by filtration and dried under vacuum at room temperature for 24 hours. Yield: 373 mg (61% of theory) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In acetonitrile; at 0℃; for 2h;Reflux; | <strong>[1187594-09-7]Baricitinib</strong> free base (533 mg, 1.4 mmol, e.g. prepared according to the teaching of WO 2009/1 14512 Al, Examples 70 or 78) and citric acid (1109 mg, 5.8 mmol) were dissolved in acetonitrile (10 mL) upon heating to reflux. The clear solution was cooled to 0 C in 2 hourswhereupon a turbid solution was obtained. Subsequently, the solvent was removed in vacuo (rotary evaporator: 30 mbar, 40 C bath temperature). The obtained residue was suspended in acetonitrile (5 mL) and treated in an ultrasonic bath for 15 mm. The suspension was then slurried at room temperature for 18 hours. The solid was collected by filtration and dried under vacuum (35 mbar) at 40 C for 24 hours. Yield: 722 mg (67% of theory) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrabutylammomium bromide; sodium hydroxide; In dichloromethane; water; at 20℃; for 1h; | Example 6 Preparation of 4-Nitrophenyl 4-(1-(3-(Cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate To a solution of baricitinib (2.40 mmol) in DCM (12 mL) is added a solution of sodium hydroxide (0.29 g, 7.20 mmol) in water (4.00 mL) and tetrabutylamonium bromide (0.08 g, 0.24 mmol). A solution of 4-nitrophenyl chloroformate (0.97 g, 4.80 mmol) in DCM (4 mL) is slowly added. The reaction mixture is stirred at room temperature for 1 h. The reaction mixture is extracted with DCM and the organic layer is washed with saturated aqueous ammonium chloride solution and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue is purified by column chromatography to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With dmap; triethylamine; In dichloromethane; for 16h;Cooling with ice; | Step 3-1-Preparation of (2S,3R,4S,5S,6S)-2-(4-((((2-(4-(1-(3-(Cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxamido)ethyl)-(methyl)carbamoyl)oxy)methyl)-2-nitrophenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl Triacetate To an ice cold solution of (2S,3R,4S,5S,6S)-2-(4-((((2-((chlorocarbonyl)(methyl)-amino)ethyl)(methyl)carbamoyl)oxy)methyl)-2-nitrophenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (1.40 g, 2.11 mmol) in DCM (50 mL) was added triethylamine (0.88 mL, 6.33 mmol) and DMAP (1.50 g, 12.66) followed by baricitinib (549 mg, 1.48 mmol). The resulting mixture was stirred for 16 h (reaction complete by TLC monitoring). The solvent was then evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel (100-200 mesh) using 2% MeOH in DCM as eluent to provide the title compound (950 mg, 45%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.4% | With dihydrogen peroxide; sodium hydroxide; In methanol; dimethyl sulfoxide; at 50℃; for 3h; | Barritinib (1.0 g, 2.7 mmol) was weighed into a 50 ml reaction flask, 15 ml of methanol and 1 ml of DMSO were added, and then 6 ml of a 1 mol/L NaOH solution and 2 ml of H 2 O 2 were added at room temperature. The reaction mixture was heated at 50 C for 3 h. After TLC confirmed the reaction was completed, cooled to room temperature and then water Ethyl acetate extraction (30 ml × 3), the organic phase was combined, washed with water (30 ml × 2), and washed with brine. Dry over anhydrous sodium sulfate for 30 min, filter, and the filtrate was evaporated to dryness. The product was obtained as a white solid 612 mg, yield 58.4%. HPLC purity was 95.98%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.0% | With hydrogenchloride; In water; at 100℃; | Weighing baritinib (8.0g, 21.5mmol) into a 500ml reaction flask, slowly adding 120ml concentrated hydrochloric acid, and heating to 100 C, After reacting for 1 to 1 h, after confirming the completion of the reaction by TLC, 120 ml of water was added, and the mixture was cooled to 0 C, and the pH was adjusted to pH 9 to 10 with a 30% NaOH solution. Extracted with ethyl acetate (100 ml × 3), and the organic layers were combined. It was washed with water (100 ml × 2), dried over anhydrous sodium sulfate for 30 min, filtered, and the filtrate was concentrated to dryness under reduced pressure at 45 C. The obtained white solid was 3.612 g, the yield was 43.0%, and the HPLC purity was 93.89%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In butanone; at 20℃; for 72h; | A 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. Further analysis, in particular the structural determination by single crystal X-ray in example 5, determined that a co-crystal between baricitinib and lactic acid had formed, wherein both molecules were present as neutral species. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5 g | With triethylamine; In acetonitrile; at 80℃; for 24h;Inert atmosphere; | A mixture of <strong>[1187594-09-7]Baricitinib</strong> (15) (10.0 g, 0.027 mol), paraformaldehyde (16.2 g, 0.54 mol of CH2O), triethylamine (54.6 g, 0.54 mol), and acetonitrile (100 mL) was heated to 80C and stirred at that temperature for ~24 h. When the reaction was complete (TLC), excess paraformaldehyde was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using ethyl acetate-hexane (1:1) as eluent. Yield 5.0 g (46%), white solid. IR spectrum, nu, cm-1: 3142, 2251, 1729, 1589, 1574, 1153, 1141. 1 H NMR spectrum (300 MHz, DMSO-d6), delta, ppm: 1.25 t (3H, J = 7.4 Hz), 3.24 q (2H, J = 7.5 Hz), 3.72 s (2H), 4.24 d (2H, J = 9.0 Hz), 4.61 d (2H, J = 9.0 Hz), 5.63 d (2H, J = 7.2 Hz), 6.67 t (OH, J = 7.4 Hz), 7.16 d (1H, J = 3.9 Hz), 7.74 d (1H, J = 3.9 Hz), 8.51 s (1H), 8.78 s (1H), 8.96 s (1H). 13C NMR spectrum (300 MHz, DMSO-d6), deltaC, ppm: 151.00, 150.75, 149.68, 139.97, 129.75, 129.54, 121.96, 116.68, 113.51, 100.13, 66.43, 59.77, 58.54, 56.10, 43.30, 26.84, 7.44. Mass spectrum: m/z 402.05 [M + H]+ . Found, %: C 51.25; H 5.10; N 24.12; S 7.85. C17H19N7O3S. Calculated, %: C 50.86; H 4.77; N 24.42; S 7.99. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In water; dimethyl sulfoxide at 5 - 60℃; | 1-8 Example 7 Preparation of Form II baricitinib co-crystal with fumaric acid 8 g of BCT and 2.75 g of FUM are dissolved in 20 mL of DMSO in a EasyMax reactor at 60 °C with continuous stirring (500 rpm). The mixture is stirred for about 15- 20 min until a clear solution is obtained. (BCT:FUM ratio is 1 : 1.1). To the clear solution, 100 mL of water is charged at 1 mL/min. Once the addition of water is completed, the temperature of the reaction mixture is reduced to 5 °C at a rate of about 1 °C/min. After 9-10 min, nucleation is observed and within the next 20-30 minutes more solids appear in the reactor. The reaction mixture is stirred overnight (18- 20 h). The solids are filtered and the wet cake is rinsed with 10 mL of water and the final rinse with 15 mL of TBME. The sample is double bagged and dried in the oven at 45 °C over the weekend. A small portion of the wet cake is analyzed by XRPD. Yield = 86%. The wet cake and dried precipitate are analyzed by XRPD, and those XRPDs are compared to the calculated XRPD for Form II baricitinib co-crystal with fumaric acid. See Figure 10. (0090) Form II baricitinib co-crystal with fumaric acid is characterized by its XRPD pattern peaks and their corresponding intensities that are listed in Table II below. (0091) Table II (0092) (0093) The angle measurements are ± 0.2° 2Q. Key defining peaks or solid-state Form II baricitinib co-crystal with fumaric acid include 7.8, 10.2, 13.8, 22.1 and 27.8 ° 2Q degrees. (0094) Figure 11 shows the TGA plot that shows (0095) Single crystals of Form II baricitinib co-crystal with fumaric acid are obtained by the instant method, and the single crystal parameters for Form II baricitinib co-crystal with fumaric acid as determined by SCXRD are: (0096) Space Group: Monoclinic, P2i/C (0097) a = 6.7 ± 1.5% (0098) b = 12.8A ± 1.5% (0099) C = 23.5A ± 1.5% (0100) a = g = 90° ± 3°, b = 97° ± 3° (0101) Volume: 2008A3 ± 3% (0102) Z=4, Z’ =1. (0103) Figure 14 shows the asymmetric unit of Form II baricitinib co-crystal with fumaric acid. Figure 15 shows the inter-molecular hydrogen bonding between baricitinib and fumaric acid molecules in Form II baricitinib co-crystal with fumaric acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetone for 5.5h; | 4 Example 4: Preparation of cocrystal of Baricitinib and T)-camphoric acid cocrystal form I Baricitinib (99 mg) and (N -camphoric acid (60 mg) were milled with addition of ethanol 96% (35 pL) in agate jar with 2 agate balls for 330 min at 25 Hz. The obtained solid corresponds to Baricitinib and (N -camphoric acid cocrystal form I as confirmed by PXRD. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile dihydrochloride salt; Ethanesulfonyl chloride With N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 5℃; for 6h; Stage #2: With ammonium hydroxide In acetonitrile at 20℃; for 4h; | 4; 9 Example-4: Process for the preparation of Baricitinib of Formula-I. Into the RBF a solution of acetonitrile, XXVI (0.05 moles) and N,N- Diisopropylethylamine (0.20 moles) were added and cooled to 0-5°C. Then Ethane sulphonyl chloride compound of Formula- VIII (0.06 moles) was added slowly and stirred for 6 hours at same temperature. After that aqueous ammonia (0.50 moles) was added allowed the reaction mass to room temperature and maintained for 4 hours. Finally, reaction mass was diluted with DM water and obtained solid material was filtered and dried afforded Baricitinib. Pure material was obtained by recrystallizing in acetonitrile DM water medium. Yield: 65%; Purity: > 99% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: 3-[4-[7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-1H-pyrazol-1-yl]-3-azetidineacetonitrile dihydrochloride; Ethanesulfonyl chloride With N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 5℃; for 6h; Stage #2: With ammonium hydroxide In acetonitrile at 20℃; for 4h; | 8 Example-8: A Process for the preparation of Baricitinib of Formula-I. Into the RBF a solution of acetonitrile, XXVIII (0.05 moles) and N, N- Diisopropylethylamine (0.20 moles) were added and cooled to 0-5°C. Then Ethane sulphonyl chloride of Formula- VIII (0.06 moles) was added slowly and stirred for 6 hours at same temperature. After that aqueous ammonia (0.50 moles) was added allowed the reaction mass to room temperature and maintained for 4 hours. Finally, reaction mass was diluted with DM water and obtained solid material was filtered and dried afforded Baricitinib. Pure material was obtained by recrystallizing in acetonitrile DM water medium. Yield: 65% Purity: > 99% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.8% | Stage #1: bis-(p-nitrophenyl) carbonate; Baricitinib In dimethyl sulfoxide at 20℃; for 7h; Inert atmosphere; Stage #2: t-butoxycarbonylhydrazine In dimethyl sulfoxide at 20℃; for 16h; Inert atmosphere; | 65.1 Step 1: Preparation of tert-butyl N- [[4- [1- [3- (cyanomethyl) -1-ethylsulfonyl-azetidin-3-yl] pyrazol-4-yl] pyrrolo [2, 3-d] pyrimidine-7-carbonyl] amino] carbamate A mixture of 2- [1-ethylsulfonyl-3- [4- (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) pyrazol-1-yl] azetidin-3-yl] acetonitrile (1486 mg, 4 mmol) and bis (4-nitrophenyl) carbonate (1337.6 mg, 4.4 mmol) in DMSO (20 mL) was stirred at room temperature for 7 hours. Then tert-Butyl hydrazinecarboxylate (634.4 mg, 4.8 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated Na2CO3 solution. The mixture was filtered. The filter cake was washed with saturated NaHCO3 solution and water. Then the filter cake was dissolved in DCM and washed with water. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol=100: 1) to afford the title compound (0.758 g, Yield: 35.8%). MS (m/z) : [M+H] + calcd for C 22H 27N 9O 5S, 530.18; found, 530.1. 1H NMR (400 MHz, CDCl 3) δ ppm 10.93 (d, J = 1.8 Hz, 1H), 8.87 (s, 1H), 8.48 (s, 1H), 8.32 (s, 1H), 7.95 (dd, J = 28.4, 4.1 Hz, 1H), 6.82 (t, J = 17.0 Hz, 1H), 6.70 (s, 1H), 4.64 (d, J = 9.3 Hz, 2H), 4.23 (t, J = 23.2 Hz, 2H), 3.42 (s, 2H), 3.09 (q, J = 7.4 Hz, 2H), 1.52 (s, 9H), 1.42 (t, J = 7.4 Hz, 3H). |
35.8% | Stage #1: bis-(p-nitrophenyl) carbonate; Baricitinib In dimethyl sulfoxide at 20℃; for 7h; Inert atmosphere; Stage #2: t-butoxycarbonylhydrazine In dimethyl sulfoxide at 20℃; for 16h; Inert atmosphere; | 65.1 Step 1: Preparation of tert-butyl N- [[4- [1- [3- (cyanomethyl) -1-ethylsulfonyl-azetidin-3-yl] pyrazol-4-yl] pyrrolo [2, 3-d] pyrimidine-7-carbonyl] amino] carbamate A mixture of 2- [1-ethylsulfonyl-3- [4- (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) pyrazol-1-yl] azetidin-3-yl] acetonitrile (1486 mg, 4 mmol) and bis (4-nitrophenyl) carbonate (1337.6 mg, 4.4 mmol) in DMSO (20 mL) was stirred at room temperature for 7 hours. Then tert-Butyl hydrazinecarboxylate (634.4 mg, 4.8 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated Na2CO3 solution. The mixture was filtered. The filter cake was washed with saturated NaHCO3 solution and water. Then the filter cake was dissolved in DCM and washed with water. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol=100: 1) to afford the title compound (0.758 g, Yield: 35.8%). MS (m/z) : [M+H] + calcd for C 22H 27N 9O 5S, 530.18; found, 530.1. 1H NMR (400 MHz, CDCl 3) δ ppm 10.93 (d, J = 1.8 Hz, 1H), 8.87 (s, 1H), 8.48 (s, 1H), 8.32 (s, 1H), 7.95 (dd, J = 28.4, 4.1 Hz, 1H), 6.82 (t, J = 17.0 Hz, 1H), 6.70 (s, 1H), 4.64 (d, J = 9.3 Hz, 2H), 4.23 (t, J = 23.2 Hz, 2H), 3.42 (s, 2H), 3.09 (q, J = 7.4 Hz, 2H), 1.52 (s, 9H), 1.42 (t, J = 7.4 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.9% | Stage #1: bis-(p-nitrophenyl) carbonate; Baricitinib With triethylamine In dichloromethane at 45℃; for 5h; Inert atmosphere; Stage #2: (S)-methyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate In dichloromethane at 45℃; for 16h; Inert atmosphere; | 64.1 Step 1: Preparation of methyl (2S)-6-(tert-butoxycarbonylamino)-2-[[4- [1- [3- (cyanomethyl) -1-ethylsulfonyl-azetidin-3-yl] pyrazol-4-yl] pyrrolo [2, 3- d] pyrimidine-7-carbonyl] amino] Hexanoate To a stirred mixture of 2- [1-ethylsulfonyl-3- [4- (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) pyrazol-1-yl] azetidin-3-yl] acetonitrile (1114 mg, 3 mmol) and bis (4-nitrophenyl) carbonate (1094 mg, 3.6 mmol) in DCM (40 mL) was added triethylamine (1.25 mL, 9 mmol). The reaction mixture was heated to 45 °C and stirred at this temperature for 5 hours. Then the reaction mixture was cooled to room temperature. (S) -Methyl 6-amino-2- ((tert-butoxycarbonyl) -amino) hexanoate (1069 mg, 3.6 mmol) was added. The reaction mixture was stirred at 45 °C for 16 hours. The solution was diluted with DCM and washed with water. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol=100: 1) to afford the title compound (1.3 g, Yield: 65.9%). MS (m/z) : [M+H] + calcd for C 29H 39N 9O 7S, 658.26; found, 658.1. 1H NMR (400 MHz, CDCl 3) δ ppm 9.93 (d, J = 7.6 Hz, 1H), 8.95 (s, 1H), 8.50 (s, 1H), 8.35 (s, 1H), 8.04 (d, J = 4.0 Hz, 1H), 6.85 (d, J = 4.1 Hz, 1H), 5.45-5.34 (m, 1H), 4.76-4.71 (m, 1H), 4.66 (d, J = 9.4 Hz, 2H), 4.63-4.56 (m, 1H), 4.52-4.42 (m, 1H), 4.28 (d, J = 9.6 Hz, 2H), 3.84 (s, 3H), 3.44 (s, 2H), 3.20-3.07 (m, 2H), 2.10-1.94 (m, 2H), 1.88-1.76 (m, 1H), 1.61-1.35 (m, 12H), 1.27 (s, 3H). |
65.9% | Stage #1: bis-(p-nitrophenyl) carbonate; Baricitinib With triethylamine In dichloromethane at 45℃; for 5h; Inert atmosphere; Stage #2: (S)-methyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate In dichloromethane at 45℃; for 16h; Inert atmosphere; | 64.1 Step 1: Preparation of methyl (2S)-6-(tert-butoxycarbonylamino)-2-[[4- [1- [3- (cyanomethyl) -1-ethylsulfonyl-azetidin-3-yl] pyrazol-4-yl] pyrrolo [2, 3- d] pyrimidine-7-carbonyl] amino] Hexanoate To a stirred mixture of 2- [1-ethylsulfonyl-3- [4- (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) pyrazol-1-yl] azetidin-3-yl] acetonitrile (1114 mg, 3 mmol) and bis (4-nitrophenyl) carbonate (1094 mg, 3.6 mmol) in DCM (40 mL) was added triethylamine (1.25 mL, 9 mmol). The reaction mixture was heated to 45 °C and stirred at this temperature for 5 hours. Then the reaction mixture was cooled to room temperature. (S) -Methyl 6-amino-2- ((tert-butoxycarbonyl) -amino) hexanoate (1069 mg, 3.6 mmol) was added. The reaction mixture was stirred at 45 °C for 16 hours. The solution was diluted with DCM and washed with water. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (DCM: Methanol=100: 1) to afford the title compound (1.3 g, Yield: 65.9%). MS (m/z) : [M+H] + calcd for C 29H 39N 9O 7S, 658.26; found, 658.1. 1H NMR (400 MHz, CDCl 3) δ ppm 9.93 (d, J = 7.6 Hz, 1H), 8.95 (s, 1H), 8.50 (s, 1H), 8.35 (s, 1H), 8.04 (d, J = 4.0 Hz, 1H), 6.85 (d, J = 4.1 Hz, 1H), 5.45-5.34 (m, 1H), 4.76-4.71 (m, 1H), 4.66 (d, J = 9.4 Hz, 2H), 4.63-4.56 (m, 1H), 4.52-4.42 (m, 1H), 4.28 (d, J = 9.6 Hz, 2H), 3.84 (s, 3H), 3.44 (s, 2H), 3.20-3.07 (m, 2H), 2.10-1.94 (m, 2H), 1.88-1.76 (m, 1H), 1.61-1.35 (m, 12H), 1.27 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 20℃; Inert atmosphere; | 4 Synthesis of compound 17: Take 11.14g (30.0mmol) of intermediate 11 and add it to 200mL solvent DCM, add chloromethyl acetate (3.91g, 36.0mmol) under nitrogen protection, slowly add Et3N (4.55g, 45.0mmol), and stir the reaction at room temperature for 2.0h, After the reaction was complete, it was washed with water (100 mL×1) and saturated brine (100 mL×1), and the organic phase was concentrated to obtain a brown solid, which was directly used in the next reaction. | |
8.8 g | Stage #1: Baricitinib With sodium hydride In dichloromethane at 0℃; Inert atmosphere; Stage #2: Chloromethyl acetate With triethylamine In dichloromethane at 5 - 20℃; Inert atmosphere; | 1 Under the protection of nitrogen, the intermediate 10 (7.43g, 0.02mol) was added to 150mL of dichloromethane, cooled to 0°C, NaH (1.20g, 0.03mol) was slowly added thereto, and the reaction was stirred for 30min, and then acetic acid chloride was slowly added thereto Methyl ester (3.25g, 0.03mol) and triethylamine (4.05g, 0.04mol), control internal temperature ≤ 5.0°C, react at room temperature for 3.0h after addition, wash with water (100mL×1), wash with saturated brine (100mL× 1), dried over anhydrous sodium sulfate and concentrated to obtain 8.80 g of crude intermediate 11, which was directly used in the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59 % | With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | 1 Method 2: Under nitrogen protection, dissolve compound 10 (0.37g, 1.0mmol) in 25mL of dichloromethane, cool down to 0°C, add triethylamine (0.15g, 1.5mmol) and chloromethyl isopropyl carbonate to the system The ester (0.18g, 1.2mmol) was reacted at room temperature for 12.0h, washed with 10mL of water, washed with saturated brine (10mL×1), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 0.29g of the product DSC4101.Yield 59%.Purity: 98.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33 % | With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | 2 Synthesis of compound 13: Under nitrogen protection, intermediate 10 (3.71g, 10.0mmol) was added to 50mL of dichloromethane, cooled to 0°C, and p-nitrophenyl chloroformate (2.41g, 12.0mmol) and triethylamine were slowly added thereto (1.52g, 15.0mmol), control the internal temperature ≤ 5.0°C, react at room temperature for 3.0h after the addition, wash with water (30mL×2), wash with saturated brine (30mL×1), dry over anhydrous sodium sulfate, and concentrate to obtain a solid. Purified by recrystallization from acetonitrile/water, and air-dried at 45°C for 12.0 hours to obtain 1.87 g of the refined product of Intermediate 13.Yield: 33%.Purity: 95.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.7 % | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 17 Synthesis of (S)-2-(1-(ethanesulfonyl)-3-(4-(7-(2-(4-isobutylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile Incorporate 1-(ethionylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile (baricitinib, 742 mg, 2 mmol), 4-dimethylaminopyridine (DMAP, 488 mg, 4 mmol), (S)-(+)-2-(4-isobutylphenyl)propionic acid ((S)-(+)-ibuprofen, 453mg, 2.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 576 mg, 3 mmol) is dissolved in dichloromethane (20 mL) and stirred for 16 h at room temperature. After the reaction, the reaction solution is diluted with dichloromethane and washed with water and saturated saline solution. The organic layer is dried with anhydrous sodium sulfate, and after filtration, the solvent is evaporated under reduced pressure to obtain a crude product. After silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:2), the target compound was obtained, white solid, 0.5 g, yield 44.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.9 % | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 18 Synthesis of (S)-2-(1-(ethanesulfonyl)-3-(4-(7-(2-(6-methoxynaphthalen-2-yl)propionyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile Convert 1-(ethionylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile (baricitinib, 371mg, 1mmol), 4-dimethylaminopyridine (DMAP, 305mg, 2.5mmol), (S)-(+)-2-(6-methoxy-2-naphthyl)propionic acid (naproxen, 230mg, 1.1 mmol) and 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) was dissolved in dichloromethane (10 mL) and stirred for 16 h at room temperature. After the reaction, the reaction solution is diluted with dichloromethane and washed with water and saturated saline solution. The organic layer is dried with anhydrous sodium sulfate, and after filtration, the solvent is evaporated under reduced pressure to obtain a crude product. Then separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1 to 1:2), the target compound was obtained, white solid, 0.25 g, yield 42.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.9 % | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 19 Synthesis of 2-(3-(4-(7-(2-(3-benzoylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethanesulfonyl)azetidin-3-yl)acetonitrile 2-[1-(ethanesulfonyl)-3-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}-1H-pyrazol-1-yl)azetidin-3-yl]acetonitrile(baricitinib, 371 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 244 mg, 2 mmol), 2-(3-benzoylphenyl)propionic acid (ketoprofen, 280 mg, 1.1 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( EDCI, 288 mg, 1.5 mmol) dissolved in dichloromethane (15 mL) with 3 h of agitation at room temperature. After the reaction, the reaction solution is diluted with dichloromethane and washed with water and saturated saline solution. The organic layer is dried with anhydrous sodium sulfate, and after filtration, the solvent is evaporated under reduced pressure to obtain a crude product. Then separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:2), the target compound, white solid, 0.2 g, yield 32.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.1 % | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 20 Synthesis of 2-(1-(ethylsulfonyl)-3-(4-(7-(2-(2-fluoro-[1,1′-biphenyl]-4-yl)propionyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile 2-[1-(ethanesulfonyl)-3-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}-1H-pyrazol-1-yl)azetidin-3-yl]acetonitrile(baricitinib, 742 mg, 2 mmol), 4-dimethylaminopyridine (DMAP, 610 mg, 5 mmol), 2-(2-fluoro-4-biphenyl)propionic acid (flurbiprofen, 537 mg, 2.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( EDCI, 576 mg, 3 mmol) dissolved in dichloromethane (20 mL) with stirring for 20 h at room temperature. After the reaction, the reaction solution is diluted with dichloromethane and washed with water and saturated saline solution. The organic layer is dried with anhydrous sodium sulfate, and after filtration, the solvent is evaporated under reduced pressure to obtain a crude product. Then separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1 to 1:2), the target compound was obtained, white solid, 0.3 g, yield 25.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.5 % | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 21 Synthesis of 2-(1-(ethylsulfonyl)-3-(4-(7-(2-(3-phenoxyphenyl)propionyl)-7H-pyrroro[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile 2-[1-(ethanesulfonyl)-3-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}-1H-pyrazol-1-yl)azetidin-3-yl]acetonitrile(baricitinib, 186 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(3-phenoxyphenyl)propionic acid (fenoprofen, 133 mg, 0.55 mmol) and 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) was dissolved in dichloromethane (10 mL) and stirred for 17 h at room temperature. After the reaction, the reaction solution is diluted with dichloromethane and washed with water and saturated saline solution. The organic layer is dried with anhydrous sodium sulfate, and after filtration, the solvent is evaporated under reduced pressure to obtain a crude product. Then separated by silica gel column chromatography (petroleum ether/ethyl acetate = 51 to 12), the target compound was obtained, white solid, 0.11 g, yield 74.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.4 % | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 22 Synthesis of 2-(1-(ethylsulfonyl)-3-(4-(7-(2-(4-(2-oxocyclopentyl)methyl)phenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile 2-[1-(ethanesulfonyl)-3-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}-1H-pyrazol-1-yl)azetidin-3-yl]acetonitrile(baricitinib, 186 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionic acid (loxoprofen 136 mg, 0.55 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144mg, 0.75mmol) was dissolved in dichloromethane (10 mL) and stirred for 17 hours at room temperature. After the reaction, the reaction solution is diluted with dichloromethane and washed with water and saturated saline solution. The organic layer is dried with anhydrous sodium sulfate, and after filtration, the solvent is evaporated under reduced pressure to obtain a crude product. Then separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 3:4), the target compound was obtained, white solid, 0.13 g, yield 43.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.6 % | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 23 Synthesis of 2-(3-(4-(4-(7-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidine-3-yl)acetonitrile 2-[1-(ethanesulfonyl)-3-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}-1H-pyrazol-1-yl)azetidin-3-yl]acetonitrile(baricitinib, 186 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin, 197 mg, 0.55 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) was dissolved in dichloromethane (10 mL) and stirred for 20 hours at room temperature. After the reaction, the reaction solution is diluted with dichloromethane and washed with water and saturated saline solution. The organic layer is dried with anhydrous sodium sulfate, and after filtration, the solvent is evaporated under reduced pressure to obtain a crude product. Then separated by silica gel column chromatography (petroleum ether/ethyl acetate = 11 to 15), the target compound, white solid, 0.18 g, yield 50.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10 % | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 20℃; | 24 Synthesis of N-(4-(2-(4-(1-(3-(cyanomethyl)-1-(ethoxesulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-oxyethyl)phenyl)acetamide 2-[1-(ethanesulfonyl)-3-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}-1H-pyrazol-1-yl)azetidin-3-yl]acetonitrile(baricitinib, 186 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-acetamidophenyl)acetic acid (Aktalide, 106 mg, 0.55 mmol) and 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) was dissolved in a mixed solvent of dichloromethane (10 mL) and DMF (2 mL) and stirred for 14 h at room temperature. After the reaction, the reaction solution is diluted with dichloromethane and washed with water and saturated saline solution. The organic layer is dried with anhydrous sodium sulfate, and after filtration, the solvent is evaporated under reduced pressure to obtain a crude product. Then separated by silica gel column chromatography (petroleum ether/ethyl acetate = 21 to 12), the target compound was obtained, white solid, 0.03 g, yield 10%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56 % | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 25 Synthesis of 2-(3-(4-(7-(2-(1,8-diethyl-1,3,4,9-tetrahydropyran[3,4-b]indol-1-yl)acetyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidine-3-yl)acetonitrile 2-[1-(ethanesulfonyl)-3-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}-1H-pyrazol-1-yl)azetidin-3-yl]acetonitrile(baricitinib, 186 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 1,8-diethyl-1,3,4,9-tetrahydropyran[3,4-b]indole-1-acetic acid (etodomic acid, 158 mg, 0.55 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) was dissolved in dichloromethane (10 mL) and stirred for 14 hours at room temperature. After the reaction, the reaction solution is diluted with dichloromethane and washed with water and saturated saline solution. The organic layer is dried with anhydrous sodium sulfate, and after filtration, the solvent is evaporated under reduced pressure to obtain a crude product. Then separated by silica gel column chromatography (petroleum ether/ethyl acetate = 51 to 11), the target compound, white solid, 0.18 g, yield 56%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.8 % | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 26 Synthesis of tert-butyl (S)-(2-(4-(1-(3-(cyanomethyl)-1-(ethosylsulfonyl)azetidine-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-oxo-1-phenylethyl)carbamate 2-[1-(ethanesulfonyl)-3-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}-1H-pyrazol-1-yl)azetidin-3-yl]acetonitrile(baricitinib, 371 mg, 1 mmol), N-Boc-L-phenylglycine (301.5 mg, 1.2 mmol), 4-dimethylaminopyridine (DMAP, 183 mg, 1.5 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( EDCI, 288 mg, 1.5 mmol) dissolved in dichloromethane (15 mL) with stirring for 16 h at room temperature. After the end of the reaction, the reaction solution is diluted with dichloromethane and washed with water and saturated saline solution. The organic layer is dried with anhydrous sodium sulfate, and after filtration, the solvent is evaporated under reduced pressure to obtain a crude product. Then separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:2), the target compound was obtained, white solid, 0.12 g, yield 19.8% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.9 % | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 30 2-2-(1-(ethylsulfonyl)-3-(4-(7-(2-(4-(1-oxoisoindolin-2-yl)phenyl)butyryl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidine-3-yl)acetonitrile Incorporate 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile (barecolitinib, 371 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 61 mg, 0.5 mmol), 2-(4-(1-oxoisoindoline-2-yl)phenyl)butyric acid (indobufen, 354 mg, 1.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol) was dissolved in dichloromethane (15 mL) and stirred for 20 h at room temperature. After the reaction, the reaction solution is diluted with dichloromethane and washed with water and saturated salt aqueous solution. The organic layer is dried with anhydrous sodium sulfate, and after filtration, the solvent is evaporated under reduced pressure to obtain a crude product. After silica gel column chromatography separation (petroleum ether/ethyl acetate = 51 to 11), the target compound was obtained, white solid, 0.46 g, yield 70.9%. |
Tags: 1187594-09-7 synthesis path| 1187594-09-7 SDS| 1187594-09-7 COA| 1187594-09-7 purity| 1187594-09-7 application| 1187594-09-7 NMR| 1187594-09-7 COA| 1187594-09-7 structure
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :