* 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.
With 4-methyl-morpholine In 1,4-dioxane at 50℃; for 4 h; Green chemistry
The intermediate (III) obtained in step E)With cyclopropanyl chloride in an amidated reaction in a system consisting of N-methylmorpholine and 1,4-dioxane,The amidation reaction time was 4 h,The amidation reaction temperature was 50 ° C,The molar ratio of the intermediate (III), cyclopropanyl chloride, N-methylmorpholine and 1,4-dioxane was 1: 2.8: 2.5:TLC plate to determine the reaction is completed, cooled to room temperature,Adding methylene chloride and water, separating the organic phase with water,Then washed with brine, dried over magnesium sulfate,Evaporated to dryness and the residue was purified over a silica gel column [elution solvent: ethyl acetate / n-hexane (3: 7 v / v)To obtain a solid yellowish solid,That is, Filgotinib, yield 91.2percentThe reaction of this step is the same as in Example 1.
With diisopropylamine In methanol; dichloromethane at 20℃; for 16 h; Inert atmosphere
The starting material [5-(4-bromomethyl-phenyl)- l ,2,4]triazolo[l ,5-a]pyridine-2- yl] amide (1 g; 2.7 mmol leq) and diisopropylamine (0.92 raL; 5.4 mmol 2eq) were dissolved in a methanol/ dichloromethane mixture (1 :5; 1.7 mL/8.5 mL) and stirred under N2 at room temperature for 10 minutes. Thiomorpholine dioxide (0.4 g; 3 mmol 1.1 eq) was added. The yellow solution was stirred at room temperature for 16 hours. The solvent was evaporated. The compound was dissolved in dichloromethane (80 mL), washed with water (30 mL) and dried over MgS04 (~5min). MgS04 was filtrated off and the product solution was evaporated, yielding a white solid raw product (1.09 g, 95percent oftheory).
92%
With N-ethyl-N,N-diisopropylamine In methanol; dichloromethane at 23℃;
[5-(4-bromomethyl-phenyl)-l,2,4]triazolo[l,5-a]pyridine-2-yl] amide (9 g; 24 mmol) was dissolved in a mixture of methanol (15 ml) and dichloromethane (75 ml). Diisopropylethylamine (8.25 ml; 48.5 mmol) was added. Thiomorpholine dioxide (3.61 g; 26.7 mmol) was added in one portion. The mixture was stirred over night at 23°C. After completion of the reaction the solvent was evaporated. The grey compound was suspended in a mixture of ethyl acetate (100 ml) and methanol (10 ml) and stirred for 2 hours at 23°C. The product was filtered dried under vacuum at 17 mbar and 50°C for 3 hours. Yield: 9.53 g (92percent of theory) purity (HPLC/UV, method A, 98.6percent tr= 2.2 min, λ=230 nm): 1H-NMR (400 MHz, DMSO-rf6) 0.74 - 0.86 (m, 4 H) 2.01 (br. s„ 1 H) 2.91 (s, 4 H) [δ ppm] 3.10 - 3.15 (m, 4 H) 3.75 (s, 2 H) 7.27 (dd, J=6.26, 1.56 Hz, 1 H)7.50 (d, J=8.21 Hz, 2 H) 7.65 - 7.71 (ni, 2 H) 7.97 (d, J=8.21 Hz, 2 H) 11.02 (br. s., 1 H) FT-IR (ATR) [cm" 1] 3288, 3230, 3188, 3088, 3057, 3003 , 2935, 2843, 2820, 1699, 1635 , 1576, 1552, 1525 , 1495, 1398, 1369, 1333, 1321 , 1298, 1269, 1215, 1186, 1 157 , 1 126, 1 1 13, 1084, 1053, 1038, 1020, 978, 962, 941 , 891 , 862, 854, 822, 779, 729, 677, 656, 631 , 625, 615 XRPD 1 st priority reflections 7. 1 , 8.1 , 10.8, 18.4, 27.3°2Θ 2nd priority reflections 14.2, 16.2, 17.2, 19.8 , 25.2°2Θ DSC endotherms (onset T) :214°C; 319°C (br.) residual solvent content 0.5.-2percent (dichloromethane)
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 90℃; for 12 h;
4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzyl)thiomorpholine 1,1-dioxo(Intermediate 1A) (20.18 g, 53 mmol),N-(5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (Intermediate 7A) (16.45 g, 59 mmol),Pd(dppf)Cl2 (3.91 g, 5 mmol),2CO3 (22.06 g, 160 mmol) was added in turn to a 250 mL three-vial flask.Then add 1,4-dioxane (100 mL),Water (25mL),The temperature was raised to 90° C. under argon protection for 12 hours.After the reaction is over,Cool to room temperatureAdd 300 mL of dichloromethane to the reaction mixture.Then wash twice with water,500mL each time,Drying the organic phase with anhydrous sodium sulfate,The organic phase is concentrated to dryness,The residue is subjected to column chromatography (eluent:Dichloromethane:methanol = 50:1) was purified to give the title product as a pale yellow solid, 11 g.
Reference:
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 22, p. 9323 - 9342
[2] Drugs of the Future, 2014, vol. 39, # 8, p. 547 - 551
[3] Patent: US2015/224199, 2015, A1, . Location in patent: Paragraph 0280-0283
[4] Patent: US2015/225398, 2015, A1, . Location in patent: Paragraph 0270; 0271; 0272; 0273
[5] Patent: WO2016/165952, 2016, A1, . Location in patent: Paragraph 0168-0169
[6] Patent: CN107759587, 2018, A, . Location in patent: Paragraph 0268-0269
4
[ 19798-81-3 ]
[ 1206161-97-8 ]
Reference:
[1] Drugs of the Future, 2014, vol. 39, # 8, p. 547 - 551
[2] Drugs of the Future, 2014, vol. 39, # 8, p. 547 - 551
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 22, p. 9323 - 9342
[4] Patent: US2015/224199, 2015, A1,
[5] Patent: US2015/224199, 2015, A1,
[6] Patent: US2015/225398, 2015, A1,
[7] Patent: US2015/225398, 2015, A1,
[8] Patent: WO2016/165952, 2016, A1,
[9] Patent: WO2016/165952, 2016, A1,
5
[ 1010120-59-8 ]
[ 1206161-97-8 ]
Reference:
[1] Drugs of the Future, 2014, vol. 39, # 8, p. 547 - 551
[2] Drugs of the Future, 2014, vol. 39, # 8, p. 547 - 551
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 22, p. 9323 - 9342
[4] Patent: US2015/224199, 2015, A1,
[5] Patent: US2015/224199, 2015, A1,
[6] Patent: US2015/225398, 2015, A1,
[7] Patent: US2015/225398, 2015, A1,
[8] Patent: WO2016/165952, 2016, A1,
[9] Patent: WO2016/165952, 2016, A1,
6
[ 1010120-55-4 ]
[ 1206161-97-8 ]
Reference:
[1] Drugs of the Future, 2014, vol. 39, # 8, p. 547 - 551
[2] Drugs of the Future, 2014, vol. 39, # 8, p. 547 - 551
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 22, p. 9323 - 9342
[4] Patent: US2015/224199, 2015, A1,
[5] Patent: US2015/224199, 2015, A1,
[6] Patent: US2015/225398, 2015, A1,
[7] Patent: US2015/225398, 2015, A1,
[8] Patent: WO2016/165952, 2016, A1,
[9] Patent: WO2016/165952, 2016, A1,
[10] Patent: CN107759587, 2018, A,
7
[ 1142936-49-9 ]
[ 1206161-97-8 ]
Reference:
[1] Drugs of the Future, 2014, vol. 39, # 8, p. 547 - 551
[2] Patent: US2015/224199, 2015, A1,
[3] Patent: US2015/225398, 2015, A1,
[4] Patent: WO2016/165952, 2016, A1,
8
[ 1142943-96-1 ]
[ 1206161-97-8 ]
Reference:
[1] Drugs of the Future, 2014, vol. 39, # 8, p. 547 - 551
[2] Patent: US2015/224199, 2015, A1,
[3] Patent: US2015/225398, 2015, A1,
[4] Patent: WO2016/165952, 2016, A1,
With diisopropylamine; In methanol; dichloromethane; at 20℃; for 16h;Inert atmosphere;
The starting material [5-(4-bromomethyl-phenyl)- l ,2,4]triazolo[l ,5-a]pyridine-2- yl] amide (1 g; 2.7 mmol leq) and diisopropylamine (0.92 raL; 5.4 mmol 2eq) were dissolved in a methanol/ dichloromethane mixture (1 :5; 1.7 mL/8.5 mL) and stirred under N2 at room temperature for 10 minutes. Thiomorpholine dioxide (0.4 g; 3 mmol 1.1 eq) was added. The yellow solution was stirred at room temperature for 16 hours. The solvent was evaporated. The compound was dissolved in dichloromethane (80 mL), washed with water (30 mL) and dried over MgS04 (~5min). MgS04 was filtrated off and the product solution was evaporated, yielding a white solid raw product (1.09 g, 95% oftheory).
92%
With N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; at 23℃;
[5-(4-bromomethyl-phenyl)-l,2,4]triazolo[l,5-a]pyridine-2-yl] amide (9 g; 24 mmol) was dissolved in a mixture of methanol (15 ml) and dichloromethane (75 ml). Diisopropylethylamine (8.25 ml; 48.5 mmol) was added. Thiomorpholine dioxide (3.61 g; 26.7 mmol) was added in one portion. The mixture was stirred over night at 23C. After completion of the reaction the solvent was evaporated. The grey compound was suspended in a mixture of ethyl acetate (100 ml) and methanol (10 ml) and stirred for 2 hours at 23C. The product was filtered dried under vacuum at 17 mbar and 50C for 3 hours. Yield: 9.53 g (92% of theory) purity (HPLC/UV, method A, 98.6% tr= 2.2 min, lambda=230 nm): 1H-NMR (400 MHz, DMSO-rf6) 0.74 - 0.86 (m, 4 H) 2.01 (br. s? 1 H) 2.91 (s, 4 H) [delta ppm] 3.10 - 3.15 (m, 4 H) 3.75 (s, 2 H) 7.27 (dd, J=6.26, 1.56 Hz, 1 H)7.50 (d, J=8.21 Hz, 2 H) 7.65 - 7.71 (ni, 2 H) 7.97 (d, J=8.21 Hz, 2 H) 11.02 (br. s., 1 H) FT-IR (ATR) [cm" 1] 3288, 3230, 3188, 3088, 3057, 3003 , 2935, 2843, 2820, 1699, 1635 , 1576, 1552, 1525 , 1495, 1398, 1369, 1333, 1321 , 1298, 1269, 1215, 1186, 1 157 , 1 126, 1 1 13, 1084, 1053, 1038, 1020, 978, 962, 941 , 891 , 862, 854, 822, 779, 729, 677, 656, 631 , 625, 615 XRPD 1 st priority reflections 7. 1 , 8.1 , 10.8, 18.4, 27.32Theta 2nd priority reflections 14.2, 16.2, 17.2, 19.8 , 25.22Theta DSC endotherms (onset T) :214C; 319C (br.) residual solvent content 0.5.-2% (dichloromethane)
82.5%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5h;
Compound 5 (60 g, 0.16 mol), thiomorpholine-1,1-dioxide (24 g, 0.18 mol),Potassium carbonate (44.6 g, 0.32 mol) and N,N-dimethylformamide (500 ml) were added to a reaction flask, heated to 80 C for 5 h, and the reaction was monitored by TLC.After cooling to room temperature, the reaction solution was slowly poured into 1500 ml of ice water, stirred for 20 minutes, filtered, and the filter cake was washed with methyl t-butyl ether and dried. Obtaining N-(5-(4-((1,1-dioxothiomorpholine)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine- 2-yl)cyclopropanecarboxamide in 56.7 g, yield 82.5%.
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere;Product distribution / selectivity;
STEP 2: Suzuki coupling 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-1,1-dioxide (1.1 eq.) was added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4:1). K2CO3 (2 eq.) and PdCl2dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 90 C. for 16 h under N2. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhyd. MgSO4 and evaporated in vacuo. The final compound was obtained after purification by flash chromatography.
With N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; at 20℃; for 16h;Inert atmosphere;
Step 3:; Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (1 eq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under N2 and thiomorpholine 1,1-dioxide (1.1 eq) was added dropwise. The resulting solution was stirred at room temperature for 16 h. After this time, the reaction was complete. The solvent was evaporated. The compound was dissolved in DCM, washed with water and dried over anhyd. MgSO4. Organic layers were filtered and evaporated. The final compound was isolated by column chromatography using EtOAc to afford the desired product.
With N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; at 20℃; for 16h;Inert atmosphere;
Step 3: Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (1 eq) and DIPEA (2 eq) are dissolved in DCM/MeOH (5:1 v:v) under N2 and thiomorpholine 1,1-dioxide (1.1 eq) is added dropwise. The resulting solution is stirred at room temperature for 16 h. After this time, the reaction is complete. The solvent is evaporated. The compound is dissolved in DCM, washed with water and dried over anhydrous MgSO4. Organic layers are filtered and evaporated. The final compound is isolated by column chromatography using EtOAc to afford the desired product.
With N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; at 20℃; for 16h;Inert atmosphere;
Step 310279] Cyclopropanecarboxylic acid [5-(4-bromomethyl- phenyl)-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-amide (1 eq) and DIPEA (2 eq) are dissolved in DCMJMeOH (5:1 v:v) under N2 and thiomorpholine 1,1-dioxide (1.1 eq) is added drop- wise. The resulting solution is stirred at room temperature for 16 h. After this time, the reaction is complete. The solvent is evaporated. The compound is dissolved in DCM, washed with water and dried over anhydrous Mg504. Organic layers are filtered and evaporated. The final compound is isolated by column chromatography using EtOAc to afford the desired product.
With N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; at 20℃; for 16h;Inert atmosphere;
[0172] Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridin-2-yl]- amide (l eq) and DIPEA (2 eq) are dissolved in DCM/MeOH (5: 1 v:v) under N2 and thiomorpholine 1,1- dioxide (1.1 eq) is added dropwise. The resulting solution is stirred at room temperature for 16h. After this time, the reaction is complete. The solvent is evaporated. The compound is dissolved in DCM, washed with water and dried over anhydrous MgSO i. Organic layers are filtered and evaporated. The final compound is isolated by column chromatography using EtOAc to afford the desired product.
With hydrogenchloride; In water; at 75 - 85℃; for 14.5h;Large scale;
Hydrochloric acid 30% aq (12.06 kg; 3.9 rel. volumes) was added to a slurry of thecompound according to Formula II (3.45 kg; 1.0 equiv.) in demineralized water (10.0 kg; 3.0 rel.volumes). Subsequently, a line rinse was performed with demineralized water (3.4 kg; 1.0 rel.volumes). The reaction mixture was heated to 80±5C for 14.5 h. After completion of the reaction(conversion :::0: 99% ), the reaction mixture was cooled to 20±5C. The reaction mixture was dilutedwith demineralized water (6.8 kg; 2.0 rel. volumes) and sodium hydroxide 33% aq (9.52 kg; 3.7 relvolumes) was dosed at such a rate that the temperature of the reactor contents remained below 35C.An additional amount of sodium hydroxide 33% aq (2.55 kg; 1.0 rel. volumes) was needed to get thepH :::0: 10. The product was filtered off, washed twice with demineralized water (1.5 rel. volumes) anddried under vacuum for 1 h, thus yielding the crude compound according to Formula I.[00167] The crude compound according to Formula I (5.70 kg) was re-slurried in demineralizedwater (23.0 kg; 8.5 rel. volumes). Hydrochloric acid 30% aq (1.65 kg; 0.7 rel. volumes) anddemineralized water (4.3 kg; 1.6 rel. volumes) were added and the reaction mixture was stirred at20±5C for 45 min. As the compound according to Formula I was not dissolved completely, thereaction mixture was stirred at 45±5C for 1 h. The reaction mixture was filtered and the residue waswashed with demineralized water (2.0 kg 0.75 rel. volumes). Sodium hydroxide 33% aq (1.12 kg; 0.6rel volumes) was added to the filtrate. An additional amount of sodium hydroxide 33% aq (1.01 kg)was needed to get the pH :::0: 10. The resulting reaction mixture was stirred at 20±5C for about 3 h.The product was filtered off, washed twice with demineralized water (4.1 kg; 1.5 rel. volumes), and twice with methyl tert-butyl ether (MTBE; 3.0 kg; 1.5 rel. volumes) and dried under vacuum for 15.5h on the filter. The product was further dried in a vacuum oven at 40±5C for 202 h, thus affording thedesired compound according to Formula I.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere;
1.1.2.4. Compound 1 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-1,1-dioxide (1.1 eq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4:1). K2CO3 (2 eq.) and PdCl2dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90 C. for 16 h under N2. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgSO4 and evaporated in vacuo. The final compound is obtained after purification by flash chromatography. Alternatively, after completion of the reaction, a palladium scavenger such as 1,2-bis(diphenylphosphino)ethane, is added, the reaction mixture is allowed to cool down and a filtration is performed. The filter cake is reslurried in a suitable solvent (e.g. acetone), the solid is separated by filtration, washed with more acetone, and dried. The resulting solid is resuspended in water, aqueous HCl is added, and after stirring at RT, the resulting solution is filtered on celite (Celpure P300). Aqueous NaOH is then added to the filtrate, and the resulting suspension is stirred at RT, the solid is separated by filtration, washed with water and dried by suction. Finally the cake is re-solubilised in a mixture of THF/H2O, treated with a palladium scavenger (e.g. SMOPEX 234) at 50 C., the suspension is filtered, the organic solvents are removed by evaporation, and the resulting slurry is washed with water and methanol, dried and sieved, to obtain the title compound as a free base.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere;
1.1.3. Compound 110271] 4-[4-(4,4,5,5-Tetramethyl-[ 1 ,3,2]dioxaborolan-2- yl)-benzyl]-thiomorpholine-1,1-dioxide (1.1 eq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4] triazolo[ 1 ,5-a]pyridin-2-yl)-amide in 1 ,4-dioxane/water (4:1). K2C03 (2 eq.) and PdC12 dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90 C. for 16 h under N2. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgSO4 and evaporated in vacuo.10272] The final compound is obtained after purification by flash chromatography.10273] Alternatively, after completion of the reaction, a palladium scavenger such as 1 ,2-bis(diphenylphosphino) ethane, is added, the reaction mixture is allowed to cool down and a filtration is performed. The filter cake is reslurried in a suitable solvent (e.g. acetone), the solid is separated by filtration, washed with more acetone, and dried. The resulting solid is resuspended in water, aqueous HC1 is added, and after stirring at room temperature, the resulting solution is filtered on celite (Celpure P300). Aqueous NaOH is then added to the filtrate, and the resulting suspension is stirred at room temperature, the solid is separated by filtration, washed with water and dried by suction. Finally the cake is re-solubilised in a mixture of THF/H20, treated with a palladium scavenger (e.g. SMOPEX 234) at 50 C., the suspension is filtered, the organic solvents are removed by evaporation, and the resulting slurry is washed with water and methanol, dried and sieved, to obtain the desired compound as a free base.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere;
[0168] 4-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-l,l-dioxide (l .leq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4: 1). K2C03 (2 eq.) and PdCl2dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90C for 16 h under N2. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgS04 and evaporated in vacuo. The final compound is obtained after purification by flash chromatography. [0169] Alternatively, after completion of the reaction, a palladium scavenger such as 1 ,2-bis(diphenylphosphino)ethane, is added, the reaction mixture is allowed to cool down and a filtration is performed. The filter cake is reslurried in a suitable solvent (e.g. acetone), the solid is separated by filtration, washed with more acetone, and dried. The resulting solid is resuspended in water, aqueous HC1 is added, and after stirring at room temperature, the resulting solution is filtered on celite (Celpure P300). Aqueous NaOH is then added to the filtrate, and the resulting suspension is stirred at room temperature, the solid is separated by filtration, washed with water and dried by suction. Finally the cake is re-solubilised in a mixture of THF/H20, treated with a palladium scavenger (e.g. SMOPEX 234) at 50C, the suspension is filtered, the organic solvents are removed by evaporation, and the resulting slurry is washed with water and methanol, dried and sieved, to obtain the desired compound as a free base.
11 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 12h;
4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzyl)thiomorpholine 1,1-dioxo(Intermediate 1A) (20.18 g, 53 mmol),N-(5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (Intermediate 7A) (16.45 g, 59 mmol),Pd(dppf)Cl2 (3.91 g, 5 mmol),2CO3 (22.06 g, 160 mmol) was added in turn to a 250 mL three-vial flask.Then add 1,4-dioxane (100 mL),Water (25mL),The temperature was raised to 90 C. under argon protection for 12 hours.After the reaction is over,Cool to room temperatureAdd 300 mL of dichloromethane to the reaction mixture.Then wash twice with water,500mL each time,Drying the organic phase with anhydrous sodium sulfate,The organic phase is concentrated to dryness,The residue is subjected to column chromatography (eluent:Dichloromethane:methanol = 50:1) was purified to give the title product as a pale yellow solid, 11 g.
With hydrogenchloride; In tetrahydrofuran; methanol; at 25 - 50℃; for 27h;Inert atmosphere;
Method of Forming a Hydrochloric Acid Salt HCl (1 M solution in THF) (655 mul, 0.65 mmol, 1.1 eq.) is added to a stirred suspension of Compound 1 (252.6 mg, 0.59 mmol, 1 eq.) and methanol (5.05 mL, 20 vols) at 50 C. The mixture is cooled to 25 C. at 1 C./min and stirred at 25 C. for 22 h. The solid is isolated by vacuum filtration and dried under suction. XRPD analysis confirmed the formation of a stable non-hygroscopic salt, containing 4-5% water, having an aqueous solubility measured at 1.9 mg/mL
With hydrogenchloride; In tetrahydrofuran; methanol; at 25 - 50℃; for 22h;
2.4.1. HC110291] HC1 (1 M solution in THF) (655 pL, 0.65 mmol, 1.1 eq.) is added to a stirred suspension of Compound 1 (252.6 mg, 0.59 mmol, 1 eq.) and methanol (5.05 mE, 20 vols) at 50 C. The mixture is cooled to 25 C. at 1 C/mm and stirred at 25C. for22h.10292] The solid is isolated by vacuum filtration and dried under suction.10293] The XRPD analysis confirmed the formation of a stable non-hygroscopic salt, containing 4-5% water, having an aqueous solubility measured at 1.9 mg/mE
2.4.3. pTSA pTSA (1 M solution in EtOH) (1.3 mL, 1.3 mmol, 2.2 eq.) is added to a stirred suspension of Compound 1 (250.7 mg, 0.59 mmol, 1 eq.) and THF (5 mL, 20 vols) at 50 C. The mixture is cooled to 25 C. at 1 C./min and stirred at 25 C. for 22 h. The solid is isolated by vacuum filtration and dried under suction. The XRPD analysis confirmed the formation of a salt, which appeared to be unstable.
In tetrahydrofuran; water; acetone; at 25 - 50℃; for 22h;
2.4.2. Maleic Acid10294] Compound 1 (246.4 mg, 0.58 mmol, 1 eq.) is suspended in 5% water in acetone (4.95 mE, 20 vols) at 25 C. and the sample is warmed to 50C. Maleic acid (1 M solution in THF) (1.2 mE, 1.22 mmol, 2.1 eq.) is added to the stirred suspension at 50 C. The mixture is cooled to 25 C. at 1 C/mm and stirred at 25 C. for 22 h.10295] The solid was isolated by vacuum filtration and dried under suction.10296] The XRPD analysis confirmed the formation of the formation of a stable non-hygroscopic salt, having an aqueous solubility measured at 0.4 mgmL.
N-(5-{4-[(1,1-dioxo-1λ6-thiomorpholin-4-yl)methyl]phenyl}-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With hydrogenchloride; In methanol; dichloromethane; water; at 20℃;
In a 250 ml round bottom flask, 2.0 g (4.7 mmol) filgotinib base were dissolved in a mixture of 160 ml dichloromethane and 4 ml methanol. While stirring at room temperature, 1 ml (10.3 mmol) 32% aqueous HC1 was added dropwise within 3 minutes. A white precipitate was formed and the mixture was stirred over night at 23 C. The white product was filtered off and washed with 40 ml dichloromethane and dried for four days at 50C / 7 mbar.Name Filgotinib hydrochloride Form BYield: 2.13 g (98% of theory)purity (HPLC/UV, method B, 98.3%tr= 2.2 min, lambda=230 nm):1H NMR (400 MHz, DMSO- ) 0.76 - 0.88 (m, 4 H) 2.01 (br. s? 1 H) 3.63 (br. s., 8[delta ppm] H) 4.53 (br. s., 2 H) 4.85 (br. s., 2 H) 7.37 (dd,7=6.84, 1.76 Hz, 1 H) 7.71 - 7.79 (m, 2 H) 7.82 (d, 7=8.21 Hz, 2 H) 8.10 (d, 7=8.60 Hz, 2 H) 11.25 (br. s., 1 H)FT-IR (ATR) [cm"1]: 3084, 2978, 2922, 2482, 1693, 1649, 1633, 1595,1560, 1522, 1500, 1473, 1448, 1396, 1356, 1311, 1277, 1250, 1184, 1167, 1130, 1063, 1026, 953, 912, 866, 839, 820, 785, 735, 715, 675, 633XRPD 1stpriority reflections 13.7, 16.2, 22.3, 23.2, 25.52ndpriority reflections 12.0, 13.2, 15.5, 18.1, 21.1The obtained dichloromethane (residual solvent) content of filgotinib hydrochloride Form B was 512 ppm.
[0176] To Compound 1 (45 g, 106 mmol, 1 eq.) under inert atmosphere is added DCM (675 mL) and methanol (225 mL). The resulting suspension is heated to 35C under stirring, and trimercaptotriazine trisodium salt 15% in water (22.5 g, 14 mmol, 0.13 eq) is added, and the resulting solution is stirred for 5h, after which the solution is filtered on 0.45muiotaeta paper under nitrogen pressure. [0177] To the filtrate is added water (50mL), and the resulting biphasic mixture is stirred at 35C for 15 min, after which period the phases are separated, and the organic layer is allowed to cool down to 20C, and washed twice more with 50 mL water. [0178] The organic layer is cooled down to 15-20C, then HC1 10% in methanol (42.4 g, 116mmol, 1.10 eq.) is added over 30 min, causing the precipitation of a solid. The suspension is further stirred at 20C for 3h, then the precipitate is isolated by filtration, the cake is washed with methanol (2x50 mL) to afford the desired compound, which is dried under vacuum at 45C for 3 h. The cake is then resuspended in water (220 mL) and stirred for 6 h at 50C, and then cooled to 15-20C. The resulting solid is separated by filtration and the cake is washed with water (2 x 30 mL), and dried at 45C for 3h to afford the desired product.
With hydrogenchloride; In dichloromethane; water; at 20 - 23℃;
0.5 g ( 1 .18 mmol) Filgotinib base prepared according to Example 1 was dissolved in 40 ml dichloromethane and the solution was stirred at room temperature. 0.13 ml (1.3 mmol) 32% aqueous HQ was added in one portion and the reaction mixture was stirred over night at 23 C. The white product was filtered off, washed with 10 ml dichloromethanr and dried for 2.5 h at 50C / 20 mbar.Name Filgotinib hydrochloride, solid Form AYield: 0.47 g (87 % of theory)purity (HPLC/UV, method A, 98.6 % tr= 2.2 min, lambda=230 nm: tr= 2.2 min, lambda=230 nm: [delta ppm] 1.17 Hz, 1 H) 7.65 - 7.94 (m, 4 H) 8.10 (d, J=8.60Hz, 2 H) 1 1.47 (br. s., 1 H) FT-IR (ATR) [cm"1] : 3092, 3036, 2985, 2943, 2847, 2609, 2434, 2378, 1693, 1647, 1597, 1572, 1524, 1502, 1454, 1396, 1348, 1335, 1302, 1284, 121 1 , 1 167, 1 128, 1067, 1030, 95 1 , 916, 870, 845, 781 , 764, 735, 721 , 631 , 606 XRPD 1st priority reflections 14.9, 19.4, 19.9, 24.8, 28.32Theta 2nd priority reflections 7.1 , 9.6, 14.3, 18.6, 26.220DSC endotherms: 33 C (br.), 188C (br.), 250C (br.) Example 8: Physical properties of filgotinib free base Forms I, II and III TGA measurements
With hydrogenchloride; In acetonitrile; at 15 - 25℃; for 48h;
19.9 mg of Filgotinib free base was suspended in 1.0 mL of acetonitrile and stirred at room temperature followed by adding 4 muL of hydrochloric acid (12 mol/L). The suspension was stirred at room temperature for 48 hours, then centrifuged and dried in vacuum at room temperature to obtain white crystalline solid of the hydrochloride. (0151) The obtained crystalline solid was Form A confirmed by XRPD. The XRPD data are listed in Table 1, and the XRPD pattern is substantially as depicted in FIG. 1.
3.0 g (7.05 mmol) filgotinib base were dissolved in 240 ml dichloromethane and the solution was stirred at 23C. 1.65 g (8.5 mmol) ethanedisulfonic acid were added in one portion and the reaction mixture was stirred for another four days at 23C. The product was filtered off, washed with 60 ml dichloromethane and dried over night at 50C/8 mbar (yield: 3.6 g).
In methanol; dichloromethane; at 20℃; for 1h;Reflux;
Filgotinib free base (0.5 g) was dissolved in dichloromethane (13 ml) and methanol (2 ml) at room temperature and heated to reflux. Fumaric acid (0.15 g) was dissolved in dichloromethane (17 ml) and methanol (3 ml). The acid solution was dropped into the solution of filgotinib and stirred for 1 hour at reflux temperature, then cooled to 23C. The reaction mixture was stirred over night, no salt formation could be observed.
Filgotinib free base (0.5 g) was dissolved in dichloromethane (13 ml) and methanol (2 ml), D-tartaric acid (0.19 g) was dissolved in dichloromethane (17 ml) and methanol (3 ml). The acid solution was dropped into the solution of filgotinib at 50C. The reaction mixture was stirred for 1 hour and then slowly cooled to 23C. The reaction mixture was stirred for 3 days, no salt formation could be observed.
In methanol; dichloromethane; at 20℃; for 1h;Reflux;
Filgotinib free base (0.5 g) was dissolved at room temperature in dichloromethane (18 ml) and methanol (2 ml) and heated to reflux. Maleic acid (0.47 g) was dissolved in dichloromethane (12 ml) and methanol (2 ml). The acid solution was dropped into the solution of the starting material; stirring was continued for 1 hour at reflux temperature. The reaction mixture was cooled to 23C. The reaction mixture was left stirring over night, no salt formation could be observed.
Filgotinib free base (0.5 g) was dissolved in dichloromethane (18 ml) and methanol (2 ml), the reaction mixture was heated to reflux. Oxalic acid (0.12 g) was dissolved in dichloromethane (4.5 ml) and methanol (0.5 ml), the acid solution was dropped into the solution of the starting material and stirred for 1 hour at reflux temperature, then cooled to 23C. The reaction mixture was stirred over night. No salt formation could be observed.
With phosphoric acid; In dichloromethane; water; at 20℃;
Filgotinib free base (0.5 g) was dissolved in dichloromethane (40 ml). Phosphoric acid (85%, 0.1 ml) was dropped into this solution at room temperature. The reaction mixture was stirred over night. A syrupy residue was formed, the solvent was decanted off and the substance was dried by evaporating (0.32 g). The solid was milled in a mortar. After storage for 4 days in a closed vial, the solid substance transformed into a syrupy substance by water uptake. In the present case the salt formation was successful, but the corresponding salt was highly instable due to its high hygroscopy and thus not applicable for a pharmaceutical formulation.
With phosphoric acid; In dichloromethane; at 20℃;
a) Filgotinib free base (0.5 g) was dissolved in dichloromethane (40 ml). Phosphoric acid (85%, 0.1 ml) was dropped into this solution at room temperature. The reaction mixture was stirred over night. A syrupy residue was formed, the solvent was decanted off and the substance was dried by evaporating (0.32 g). The solid was milled in a mortar. After storage for 4 days in a closed vial, the solid substance transformed into a syrupy substance by water uptake. In the present case the salt formation was successful, but the corresponding salt is highly instable due to its high hygroscopy and thus not applicable for a pharmaceutical formulation.
With sulfuric acid; In methanol; dichloromethane; water; at 35℃; for 0.5h;
0.5 g (0.12 mmol) filgotinib base were added to 40 ml dichloromethane and heated to reflux (approx. 35C). 2 ml methanol were added and 0.4 ml sulfuric acid (30% aqueous solution) were added dropwise at this temperature. The reaction mixture was stirred for 30 min. at 35C; during stirring a white precipate was formed. Then the reaction mixture was slowly cooled down to 23 C under stirring. The product was filtered off, washed with 10 ml dichloromethane and dried over night at 50C / 8 mbar. Name Filgotinib sulfate, Form S2Yield: 0.74 g (100% of theory)purity (HPLC/UV, method B, 97.5%tr= 2.2 min, lambda=230 nm):1H NMR (400 MHz, DMSO-0.3 H (imp.)) 3.60 (m, 4 H) 3.69 (m, 4 H) 4.59 (s, 2 H) 5.73 (m, 0.06 H (imp.)) 6.85 - 7.40 (br. s, 8 H) 7.49 (dd, J=7.43, 1.17 Hz, 2 H) 7.56 - 7.63 (m, 1 H) 7.70 - 7.83 (m, 4 H) 7.84 - 7.95 (m, 1 H) 7.97 - 8.06 (m, 0.23 H (imp.)) 8.10 (d, J=8.21 Hz, 2 H) 11.67 (br. s., 1 H)FT-IR (ATR) [cm"1]: 3421, 3205, 3109, 3010, 2985, 2935, 2602, 2118,1703, 1647, 1597, 1570, 1506, 1460, 1446, 1402, 1392, 1331, 1309, 1230, 1200, 1155, 1132, 1068, 1045, 1018, 953, 912, 866, 847, 796, 785, 731, 710, 683, 633XRPD 1stpriority reflections 4.5, 6.0, 11.4, 16.7, 22.62ndpriority reflections 10.5, 15.8, 19.3, 20.9, 25.6DSC br. endotherm (30-120C); br. endotherm (240-320C) with peaks at 267, 283 and 300C;
With 4-methyl-morpholine; In 1,4-dioxane; at 50℃; for 4h;Green chemistry;
The intermediate (III) obtained in step E)With cyclopropanyl chloride in an amidated reaction in a system consisting of N-methylmorpholine and 1,4-dioxane,The amidation reaction time was 4 h,The amidation reaction temperature was 50 C,The molar ratio of the intermediate (III), cyclopropanyl chloride, N-methylmorpholine and 1,4-dioxane was 1: 2.8: 2.5:TLC plate to determine the reaction is completed, cooled to room temperature,Adding methylene chloride and water, separating the organic phase with water,Then washed with brine, dried over magnesium sulfate,Evaporated to dryness and the residue was purified over a silica gel column [elution solvent: ethyl acetate / n-hexane (3: 7 v / v)To obtain a solid yellowish solid,That is, Filgotinib, yield 91.2%The reaction of this step is the same as in Example 1.
With triethylamine; at 5 - 20℃;
4-(4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzyl)thiomorpholine-1,1-dioxide compound of Formula (IV) (10.83 g 33.3 mmol.) in MDC (150 ml) at 5 C., was added triethylamine (11.6 ml, 83.3 mmol) followed by cyclopropanecarbonyl chloride of Formula (V) (83.3 mmol). The reaction mixture was then allowed to warm to ambient temperature and stirred until all starting material was consumed. If required, further Triethyl amine (4.64 ml, 33.3 mmol) and cyclopropanecarbonyl chloride of Formula (V) (33.3 mmol) was added to ensure complete reaction. After standard work up procedure solvent was evaporated and crude solid was purified in mixture of dimethyl acetamide-toluene. Further after purification resulted solid was treated with aqueous ammonia solution (50 ml) and stirred at ambient temperature to hydrolyze any bis-acylated product. Product was obtained filtration. Further crude Filgotinib was purified in acetone (50 ml). The solid was collected by filtration, washed with acetone (50 ml) and dried in vacuum to give pure filgotinib
N-(5-(4-((1,1-dioxothiomorpholine)methyl)phenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropanethiocarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.8 g
With Lawessons reagent; for 7h;Inert atmosphere; Reflux;
N-(5-(4-((1,1-Dioxothiomorpholine)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-one Base) cyclopropanecarboxamide (1.00 g, 2.4 mmol) was added to a 50 mL single-mouth bottle,To which toluene 20 mL was added in sequence,Lawson's reagent (0.48 g, 1.2 mmol).Under argon protection,The mixture was refluxed for 7 hours.After the reaction is over,Cool to room temperatureThe mixture was suction filtered and the filtrate was concentrated to dryness under reduced pressure.The residue was purified by column chromatography (eluent: dichloromethane:methanol = 50:1).The title product was obtained as a yellow solid 0.8g.
N-(5-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide maleate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In water; acetone; at 50℃; for 16h;
Filgotinib maleate Form I was prepared by heating N-(5-(4-((1,1- dioxidothiomorpholino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- yl)cyclopropanecarboxamide with 2.1 mol. eq. of maleic acid in acetone/water (95:5 v/v) at about 50 C for about 16 hours. Afterwards, the reaction contents were cooled to about 20 C over about 1.5 hours and held at about 20 C for about 2 hours. Next, the reaction contents were filtered. The wet cake was washed with acetone and dried under vacuum at about 50 C with agitation.
4-[(4-bromophenyl)methyl]-1,4-thiazinane 1,1-dioxide[ No CAS ]
N-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylcyclopropanecarboxamide[ No CAS ]
[ 1206161-97-8 ]
Yield
Reaction Conditions
Operation in experiment
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; at 140℃;
4-(4-bromobenzyl)thiomorpholine1-dioxide of Formula (XI) (2 eq) was added to a solution of N-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]Triazolo[1,5-a]pyridine-2-yl] cyclopropanecarboxamide of Formula (X) in 1,4-dioxane/water (5:1). potassium carbonate K2CO3 (2 eq.) and PdCl2dppf (5%) was added to the solution. The resulting mixture was then heated at 140 C. till starting material consumed. After completion of reaction water was added and the solution was extracted with ethyl acetate. Organic layers was dried over anhydrous MgSO4 and evaporated under vacuum to afford filgotinib.
Add compound 6 (49.36g, 100mmol) and ethanol (247mL) to the three-necked flask. After stirring, add 25% ammonia water (34.06g, 500mmol), and react at room temperature for 6-8 hours. After the reaction, concentrate and remove part of the solvent. The pH was adjusted to 6 to 7 by hydrochloric acid, slowly cooled to 0 to 5 C, and slurried, filtered, and the crude product was recrystallized with ethanol and water to obtain a figatinib product 9 (40.13 g, 94.3%, purity 99.86%).
N-(5-(4-formylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide[ No CAS ]
[ 59801-62-6 ]
[ 1206161-97-8 ]
Yield
Reaction Conditions
Operation in experiment
88.5%
Add compound 8 (30.63 g, 100 mmol) to a three-necked flaskAnd <strong>[59801-62-6]thiomorpholine 1,1-dioxide hydrochloride</strong> 5b (18.88 g, 110 mmol),Add acetonitrile (153mL),Add triethylamine (12.14g, 120mmol),After stirring for 1 to 2 hours, trifluoroacetic acid (22.80 g, 200 mmol) was added.After stirring for 30 minutes, triethylsilane (23.26 g, 200 mmol) was added dropwise.After stirring at room temperature for 30 minutes, the temperature was gradually raised to reflux for 8 to 10 hours.At the end of the reaction, some solvents were removed,Water (306 mL) was added slowly and stirred,Ethyl acetate (153 mL) was added and extracted twice.Combined organic phases were washed once with water (77 mL),Concentrate to dryness and add ethanol (153mL)And water (306mL), heated to 55 60 ,Slow cooling crystallizationfilter,Collect solids to dry,DefertinibProduct 9 (37.66g, 88.5%,Purity: 99.74%).
Stage #1: 4-(4-bromobenzyl)thiomorpholine 1,1-dioxide With magnesium In tetrahydrofuran at 40 - 55℃;
Stage #2: N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide With bis(acetylacetonate)nickel(II) In tetrahydrofuran at -20℃; Reflux;
1-2 Example 1
Add 0.60 g of magnesium chips (1.5 eq.) to the reaction flask. and 2 mL of THF, warmed to 40 °C. Weigh 4.5g of intermediate (II) (X is Br) dissolved in 18mL THF, slowly add it dropwise to the system, raise the temperature to 55 °C and continue to add dropwise, reflux stirring overnight.0.5g of intermediate (IV) (X is Br) and 0.12g of Ni(acac)2were added to 10mL THF, cooled to -20 °C dropwise plus the above Grignard reagent solution, reflux reaction overnight, the system was poured into 5mL of water, solid precipitation, filtration, drying to obtain compound (I), purity 99.86%, yield 81%, nickel residue 0.1ppm.